THE NEW AGE OF ALZHEIMER’S

CONTRIBUTIONS FROM: BILL GATES global health philanthropist

ELIAS ZERHOUNI HILARY EVANS

former NIH director U.K. Alzheimer’s leader

THE NEW AGE OF ALZHEIMER’S

The soaring burden of dementia threatens global health. Science is paving new paths to solutions.

POWERFUL NEW DIAGNOSTICS

ALZHEIMER’S BALLOONING COSTS

THE CAREGIVER’S DILEMMA

KOTO FEJA/GETTY IMAGES

[ PUBLISHER’S LETTER ]

DEAN ROHRER C/O THEISPOT

he hospice nurse who, in the final A Crazy T

days of my father’s care, was one of Little Thing

our family’s rocks of stability, put two fingers gently to Called Hope

his neck as a last read of his vital signs. “Yes,” she said, reassuringly and tenderly, as she looked at me BY JEREMY ABBATE

and my mother, “he’s gone.”

It was a humid afternoon in August 2017. We were gathered in the family room of the New Jersey home in which I had grown up, leaning over a medical bed set up for my father in the final six weeks of his life.

“It’s a very

sad condition… science, hopefully,

will one day cure it.”

While a day of haunting sor- row, we had cause to be grateful: my father, diagnosed with fronto- temporal dementia (FTD) earlier that spring, which had developed into full-blown ALS, went quickly. His earliest perceptible symptoms appeared in February of that year, and he took his last breath in Au- gust. He avoided the fate of his two older sisters, his mother, and his father, each of whom suffered a long, protracted, heart-breaking decline from Alzheimer’s disease.

I was 11 years old when I first meaningfully heard of Alzheimer’s. Enroutetoavisitwithmygrand- parents, my mother warned me not to be surprised if my grandfather didn’t recognize me or remember my name. “It’s a very sad condi- tion,” she explained, but added that “science, hopefully, will one day cure it.”

That’s how the trajectory of devastation from Alzheimer’s be- gan on my father’s side of the fam- ily, as it has for millions like us across the country and the world: all of us seeking that elusive hu- man comforter, hope.

SCIENTIFIC AMERICAN CUSTOM MEDIA 3

In the 1980s, as the nascent era of modern biotechnology began offering better tools for conditions such as diabetes and cancer (and, soon after, HIV and many other diseases), research into Alzheimer’s started to ramp up in earnest. The human neurological system is by nature difficult to study, and clarifying the precise pathogen- esis and modulation of a disease as complex as Alzheimer’s pre- sented a Herculean challenge for researchers and allied healthcare communities across the world at the time.

Back then, patients and fami- lies had little in the way of hope. We were told to maybe avoid cer- tain substances like aluminum in deodorants. Early genetic tests could offer some insight into gene variants that might imply more likelihood of the disease. Memory- enhancing drugs called cholines- terase inhibitors that came on the scene in the 1990s were minimally effective—they were, as my physi- cian friends confessed, prescribed more for the benefit of the family than the patient.

Real progress seemed far off. At the time, Alzheimer’s was always diagnosed well after symptoms appeared, and the emotional, fi- nancial, and logistical burdens on patients and families made the di- agnosis a moment of dread. With decline and heartache on the hori- zon, facing Alzheimer’s then was like holding the ocean back with a broom.

While the arc of scientific re- search is long, it did eventually bend towards progress. At the beginning of the current decade, while the world was in the throes of another urgent health crisis, a global viral pandemic, those of us tracking milestones in Alzheimer’s began to realize we were in a much different place than we had been a few years earlier. For the

first time, real hope, real progress, had appeared on the horizon.

Progress came in stages and had a powerful cumulative effect. Clinical data that had been per- colating for years were revealing an ever-sharper picture of how lifestyle and nutrition choices can alter one’s susceptibility to Alzheimer’s. A much more effec- tive diagnostic arsenal and better tools for measuring neural activ-

There is a long journey ahead, to be sure. But there is also a palpable sense that hope is at hand.

ity were generating penetrating insights into brain biology and brain health.

Meanwhile, the field achieved an incredibly important mile- stone: the first disease-modifying therapies for Alzheimer’s. While they’re not a cure and they have potential side effects, these thera- pies are no small feat: They may have a significant effect on slow- ing disease progression for those in Alzheimer’s early stages. This is cause for celebration after several frustrating decades of nothing.

In the context of other recent scientific and social advances— real progress in gene therapy and gene editing; a post-pandemic ethos of collaboration among re- searchers across borders; a pro-

found awareness of how govern- ments can catalyze and de-risk much-needed innovation during a crisis—the landscape for Alzhei- mer’s is no longer bleak. More early diagnosis and even more attention on phenomic factors (the sum total of our genetic, environmental and behavioral inputs) will no doubt keep up the momentum. There is a long journey ahead, to be sure. But there is also a palpable sense, for those deeply embedded in the community and the public in gen- eral, that hope is at hand.

As someone ensconced in the world of science media and who attends several annual conferenc- es, I happily come across cham- pions of healthcare frequently. It was at one such conference that I met Phyllis Barkman Ferrell, an advisor to this special edi- tion and media project from Sci- entific American Custom Media, and a kindred spirit in the fight against Alzheimer’s who has also personally been affected by the disease. Phyllis introduced me to the team at the Davos Alzheimer’s Collaborative (DAC), a partner in this media effort and an organi- zation emblematic of the global scale to which we need to direct our efforts, including its dynamic chairman, George Vradenburg, with whom I had an instant con- nection because of to our shared passion for this topic.

This special edition and DAC partnership are dedicated to all our families, and to the many families and patients worldwide seeking progress on this hor- rible disease. It is an exploration and celebration of what we can achieve if we work together. And it is, above all, a celebration of what I’ve been chasing since I was 11 years old: a new era of hope.

Jeremy Abbate is the publisher of Scientific American.

4 THE NEW AGE OF ALZHEIMER’S

[ CONTENTS ]

on the cover:

illustration by Harol Bustos

8 Seize This Global Moment

Defeating Alzheimer’s is now possible, if we meet the global health challenge the disease has created.

BY GEORGE VRADENBURG AND OLIVIER SCHWAB

10 A Seismic Shift

in Alzheimer’s

Recent advances in early detection and treatment have galvanized scientists and given hope to patients.

BY DAVID H. FREEDMAN

17 Stopping Alzheimer’s

Ahead of Symptoms

Can drugs given early stave off cognitive decline?

BY DAVID H. FREEDMAN

21 “You should know,

I’m not a saint.”

Most caregivers of people with Alzheimer’s find themselves behaving in counterproductive ways. The disease affects their brains, too.

BY DASHA KIPER

24 The Ten Trillion

Dollar Disease

A new model of Alzheimer’s predicts a staggering economic burden and justifies major invest- ments in research, testing, treat- ments and public-health outreach. BY DAVID BLOOM, SIMIAO CHEN AND ARINDAM NANDI

INFOGRAPHIC

28 The Ballooning Economic

Impact of Dementia

A new model predicts Alzheimer’s and other dementias will cost

$17 trillion a year by 2050.

SCIENTIFIC AMERICAN CUSTOM MEDIA 5

[ CONTENTS ]

32 A Marathon Journey from Lab to Clinic

How 20 years of molecular detective work led to the first effective Alzheimer’s drugs. BY ESTHER LANDHUIS

INFOGRAPHIC

36 Alzheimer’s Impact

on the Brain

The latest neuroscience tracks where the disease begins and how it progresses.

42 An Alzheimer’s Test

for Everyone

Annual checkups may soon include a blood test that screens people for Alzheimer’s, ushering in a new era of treatments.

BY SUZANNE SCHINDLER

INFOGRAPHIC

47 HowtoDetectAlzheimer’s Before Symptoms Appear New technologies that catch the earliest signs of dementia will be critical for slowing, and one day stopping, disease progression.

48 Beyond Pen and Paper Digital cognitive tests designed to spot early signs of Alzheimer’s are beginning to hit the market.

BY ADAM PIORE

INFOGRAPHIC

51 Gateway to the Brain

The eyes are windows to the central nervous system and may offer new, noninvasive screening methods.

INFOGRAPHIC

52 Risk Factors for Alzheimer’s Genes and age play a big role in susceptibility to the disease, but choices make a difference, too.

54 A Grassroots

Approach to Diversity Community engagement is a must for ensuring clinical trial diversity and effective treatments for all.

BY SIMAR BAJAJ

Q&A

58 “We need genomics

at a global scale”

Research on diverse populations is essential to beat a disease as complex as Alzheimer’s, says Elias Zerhouni.

BY FRED GUTERL

64 The Urgent

Challenge of Scale

To bring new tests and treatments to the people who need them, healthcare systems must transform how they approach dementia care. BY HILARY EVANS AND JOHN BELL

INFOGRAPHIC

68 The Approaching Alzheimer’s Wave

Dementia is on the rise in every region of the world, with vast implications for public health.

6 THE NEW AGE OF ALZHEIMER’S

LESSONS FROM AROUND THE GLOBE

Community-based programs are exploring new ways of managing Alzheimer’s care.

70 A Gentle Sleight of Hand

The village of Volta Redonda in Brazil has built a model day-care center for Alzheimer’s patients. BY MAC MARGOLIS

72 Preaching Brain Health

to Young and Old Alike

Scotland is putting in place an infrastructure for preventing Alzheimer’s.

BY WILLIAM UNDERHILL

74 It Takes a Village

Community leaders in Kenya

are leading the charge to increase Alzheimer’s awareness and reduce stigma.

BY APRIL REESE

76 Teaching Good

Brain Hygiene

In Japan, where more than 90,000 people are 100 years or older, clinicians are advocating lifestyle habits that reduce the risk of Alzheimer’s.

BY MIHOKO IIDA

78 Taking It to the Streets In Armenia, clinicians travel the

countryside in a minivan, conducting tests for Alzheimer’s. BY APRIL REESE

Q&A

80 “We’re at a tipping

point with Alzheimer’s”

Bill Gates talks about his own experience as a caregiver and what needs to be done to fight this disease.

SCIENTIFIC AMERICAN

PUBLISHER:

JEREMY ABBATE

EDITORIAL DIRECTOR, PARTNERSHIPS & CUSTOM MEDIA: CLIFF RANSOM

SENIOR EDITOR,

PARTNERSHIPS & CUSTOM MEDIA: DAN FERBER

CONSULTING EDITOR:

FRED GUTERL

ART DIRECTOR:

JOELLE BOLT

DATA VISUALIZATION DESIGNER:

KATIE PEEK

DIRECTOR OF CONTENT PARTNERSHIPS: MARLENE STEWART

SENIOR PROJECT MANAGER:

LEEOR COHEN

PROJECT MANAGER:

WILL MARLOW

DAVOS ALZHEIMER’S COLLABORATIVE

FOUNDING CHAIRMAN OF THE BOARD: GEORGE VRADENBURG

HEALTHCARE SYSTEM PROGRAM ADVISOR: PHYLLIS BARKMAN FERRELL

PROJECT ADVISORS:

SUSAN OLIVER KATIE SELZLER

THIS SPECIAL EDITION WAS PRODUCED IN PARTNERSHIP WITH THE DAVOS ALZHEIMER’S COLLABORATIVE BY SCIENTIFIC AMERICAN CUSTOM MEDIA,

A DIVISION SEPARATE FROM THE MAGAZINE’S BOARD OF EDITORS.

SPECIAL THANKS TO BRIGHTFOCUS FOUNDATION, GATES VENTURES, GHR FOUNDATION AND

THE MORNINGSIDE FOUNDATION, ALL OF WHOM HELPED SUPPORT THIS PROJECT.

FIND US ONLINE AT SCIAM.COM/ALZ. QUESTIONS? COMMENTS? WRITE US AT ALZ@SCIAM.COM

SCIENTIFIC AMERICAN CUSTOM MEDIA 7

Seize This Global Moment

Defeating Alzheimer’s is now possible, if we meet the global health challenge the disease has created.

BY GEORGE VRADENBURG OAND OLIVIER SCHWAB

n behalf of the 55 million peo- ple worldwide who live with Alzheimer’s dis- ease, the mil- lions more who shoulder the burden of care and loss, and the younger generations whose futures are clouded by the threat of this disease, we issue a call to action.

The time is ripe. For the first time, we have an opportunity to defeat this disease, which robs so many otherwise healthy people of their memories and their identi- ties and causes so much suffering and loss to them, their loved ones and society at large.

In recent years, scientists have made startling advances in their ability to detect Alzheimer’s disease in the early stages, when treatments are most effective. Drugs are now available that can slow the prog- ress of the disease, having gone from the lab to pharmacy shelves, and more are in the pipeline.

The arrival of these twin ad- vances in testing and treatments has galvanized medical research- ers, entrepreneurs and healthcare professionals. Several big phar- maceutical firms that had backed away from the disease, because it was so complex that it defied quick solutions, are once again making big investments. Biotech firms are working to commer- cialize new technologies, such as blood biomarker tests and cogni- tive tests that can help in diagnos- tics and screening. What’s more, regulators have shown a new willingness to move drugs quick- ly through the approval process, which is spurring innovation.

DANIEL HERTZBERG C/O THEISPOT

8 THE NEW AGE OF ALZHEIMER’S

This good news brings a new challenge: getting these tests and treatments to the millions of peo- ple in all corners of the world who need them. We formed the Davos Alzheimer’s Collaborative (DAC) in part to address this challenge.

Part of this task involves bol- stering our ability to detect Alz- heimer’s early in the disease. Sev- eral blood tests that are currently on the market can measure tell-

take?” Doctors will need to fig- ure out how to build Alzheimer’s testing into their routine clinical practice. DAC is helping them do exactly that.

Rectifying inequities is criti- cal. So far, researchers developing treatments and tests have focused on people of northern European descent, neglecting the rest of the world, where the vast majority of Alzheimer’s patients are to be

Europe, China, India and other nations need to join the U.S., U.K. and others in the fight against this disease.

The World Economic Forum and the Global CEO Initiative on Alzheimer’s Disease came togeth- er to form DAC, because we need an international organization that can coordinate an approach to Alzheimer’s disease that resem- bles the global effort to fight infec- tious disease. DAC was modeled on organizations such as Gavi, the Vaccine Alliance; The Coalition for Epidemic Preparedness Innova- tions and The Global Fund, which were formed as mechanisms for battling malaria, polio, influenza and other infectious diseases around the world.

Defeating Alzheimer’s will re- quire a massive cooperative effort. DAC is already working to speed innovation and prepare health- care systems to implement new technologies and strategies. We are enlisting corporate executives, gov- ernment leaders and nongovern- mental organizations in an effort to ease the burden of this disease and end the suffering it causes.

In the following pages you will read about our efforts thus far to make health systems better able to detect the disease early, reach un- derserved populations and to find new, innovative ways of bringing more providers to the frontlines.

Leveraging what we are learn- ing from around the world, we are calling on governments to increase their investments in research, healthcare and treatments. Work- ing together, we can beat this dis- ease rapidly and comprehensively.

George Vradenburg is the founding chairman of the Davos Alzheimer’s Collaborative. Olivier Schwab is the managing director of the World Economic Forum.

“We are calling on governments worldwide to increase their investments in research, healthcare and treatments.”

tale proteins, and more are due in the coming months. We need to make these tests cost-effective and plentiful.

Even though much of the tech- nology needed for early detection is already in place, policymakers are underestimating the resources and assistance that clinics, doc- tors’ offices and public-health of- ficials will require to adopt and implement early detection.

Putting tools in the hands of consumers is another effective strategy that could be helpful in early detection. Digital assessment tools are now available that allow you to test yourself for cognitive impairment—whether it’s memo- ry, judgment or orientation. Such tests can help manage the screen- ing workload in clinics.

We also need to raise public awareness about the new outlook for Alzheimer’s, so that people know there’s something they can do about the disease other than fear it. People should be asking their doctors, “How is my brain health? Is there a blood test I can

found. This is unfair, and it is also bad science, because it leaves out information contained in the full panoply of human genetic diver- sity. Research organizations are making efforts to rectify this gap, but much remains to be done.

Healthcare systems around the world, already strained by the growing prevalence of Alzheimer’s and other diseases, will need help in handling the new protocols for screening and treatment.

To seize this global moment, we must work together. At pres- ent, the field of Alzheimer’s is fragmented. Academics work with their cohorts, businesses have their product strategies, governments focus on their own citizens. This compartmentalization is a wasted opportunity to pool our knowledge and scale our resources.

Governments around the world need to step up their game. The U.S. National Institutes of Health spent about $400 million a year on Alzheimer’s disease in 2010; it now spends $3.7 billion. No other government or region comes close.

SCIENTIFIC AMERICAN CUSTOM MEDIA 9

A Seismic Shift in Alzheimer’s

Recent advances in early detection and treatment have galvanized scientists and given hope to patients. BY DAVID H. FREEDMAN

ILLUSTRATIONS BY HAROL BUSTOS

10 THE NEW AGE OF ALZHEIMER’S

Not long ago, the only way to tell Anenormoustoll

whether a patient with dementia had Alzheimer’s disease was to do an autopsy for the presence of amy- loid plaque and other signs of degen- eration in the brain. In recent years, new tests can detect the presence of

amyloid, a telltale protein of Alzheimer’s, and other biological signs long before the onset of symptoms. Soon, doctors may routinely make definitive diagno- ses of Alzheimer’s with a simple blood test, even be- fore symptoms of dementia become apparent.

An early diagnosis of Alzheimer’s is not worth much if there’s nothing you can do about it. But new

effective treatments that slow

ease have become available:

the drug lecanemab, recently

approved by the FDA, and a

new one called donanemab,

which slowed cognitive de-

cline in trials. The availabil-

ity of effective treatments,

together with technologies

for detecting Alzheimer’s in

the early stages, when those

treatments can be most ef-

fective, have radically changed the outlook for Alz- heimer’s patients and their loved ones. The notion of attacking Alzheimer’s in the brain before clini- cal symptoms emerge, long merely an aspiration, is starting to look like a practical strategy.

Advances in early detection and treatment come as welcome news, but they imply a looming public- health challenge. Being able to screen for Alzheimer’s and administer treatments before symptoms arise would vastly increase the number of people who need attention. Public-health institutions are almost universally inadequate for the task. There are large disparities in the impact of Alzheimer’s and in access to care in the U.S. and around the world. Pilot pro- grams in communities around the world are showing how it might be done.

Meanwhile, the new optimism rippling through the research field is palpable. “Having been in this field for 20 years, the idea that I can finally offer treatments that biologically slow the disease is in- credibly exciting,” says Gil Rabinovici, who directs the Alzheimer’s Disease Research Center at the Uni- versity of California, San Francisco. “There’s a lot more work to do, but the feeling is that our under- standing and ability to measure and treat the disease is coming together in a new way.”

AboutoneinnineAmericansover65haveAlzheimer’s disease, according to figures from the Alzheimer’s Association. The numbers are higher for several seg- ments of the population, including women, Black Americans and Hispanics. The number of people with Alzheimer’s is expected to more than double in 25 years.

It is a cruel, relentless disease. “It progressively robs you of who you are,” says neuroscientist Donna Wil- cock, director of Indiana University’s Center for Neu- rodegenerative Disorders. Families carry much of the weight, she adds. The annual cost of Alzheimer’s care in the U.S. has reached $345 billion, the Alzheimer’s Association estimates—and that doesn’t count the

the progress of the dis-

“The feeling is that our understanding and

ability to measure and treat the disease is coming together in a new way.”

$340 billion worth of unpaid care put in by an estimated 11 million family members and other caregivers of U.S. Alzheimer’s patients in 2022. Other estimates run even higher (see “The Ten Trillion Dollar Disease,” on page 24).

Modern medicine has made enormous strides in treating cancer, diabetes,

heart disease, and even other neurodegenerative diseases such as Parkinson’s and multiple sclerosis. But for years, everything medicine could throw at Alzheimer’s seemed to bounce off. The main research strategy has been to try to come up with drugs that attack the plaque that for more than a century has been known to be present in the brain tissue of de- ceased Alzheimer’s patients. But the dozens of ex- perimental drugs that reduced brain plaque in mice with Alzheimer’s-like symptoms failed to make any detectable difference in cognitive decline in human drug trials.

Then, in 2021, a leap of progress came with the Food and Drug Administration approval of adu- canumab, an amyloid-beta-attacking monoclonal antibody—a lab-made version of an antibody found in the human immune system. Aducanumab was the first drug ever approved for slowing cognitive decline in Alzheimer’s patients. But it was a contro- versial decision, in part because trial data showed at best hints of a possible small average slowing in cognitive decline.

Much of that uncertainty evaporated in Janu- ary 2023, when the FDA approved a second plaque- fighting monoclonal antibody, lecanemab. This time, the regulators saw clear evidence that on average the

SCIENTIFIC AMERICAN CUSTOM MEDIA 11

drug slowed the cognitive decline in patients with early symptoms of Alzheimer’s. And that thrilling news was still reverberating through the research and patient communities when data released in July 2023 from a phase 3 trial of a third monoclonal antibody, donanemab, showed even better results, slowing the decline in memory and thinking by 35 percent compared to placebo. Almost half the study subjects who received donanemab showed no wors- ening of symptoms during a year of treatment, com- pared to only 29 percent in the placebo group.

ing amyloid beta plaque in living human patients have been around since 2004, but the early versions required massive machines that cost more than a million dollars to install, and even then the results didn’t give a reliable diagnosis of Alzheimer’s dis- ease. It wasn’t until 2017 that affordable PET scans became capable of reliable plaque-based Alzheimer’s disease diagnosis.

When clinicians and researchers started accumu- lating results from those scans, they discovered two things. First, as many of 30 percent of people diag-

“This is one of the things that patients and families say is im- portant to them—to stay at the same level longer to keep doing what they enjoy doing,” says Mark Mintun, who heads neuroscience research and development at Eli Lilly, the pharmaceutical compa- ny that developed donanemab.

“Alzheimer’s progressively robs you of who you are.”

nosed with Alzheimer’s disease based on cognitive assessments didn’t have high levels of the plaque, which meant they had a different type of dementia and had been misdiagnosed. Thus, some of the plaque-reducing drugs that had failed in earlier trials probably hadn’t done as well as they might

The sudden appearance of helpful treatments has been revitalizing for both the patient and research communities, says Indiana University’s Wilcock. “Pa- tients and families had lost a lot of hope, and this re- stores it,” she says. “I truly believe it’s the beginning of the successful treatment of the disease.”

Continually better drugs are likely to follow in a steady stream over the coming years and decades, experts say. Alzheimer’s research may be similar to multiple sclerosis, another complex neurological disease. The first approved drugs in the 1990s were about 30 percent effective, and now several drugs are more than 80 percent effective.

Diagnostics breakthroughs

Several factors have led to the sudden emergence of effective drugs. One is that the newer drugs are aiming at the right kind of amyloid plaque. There are many types, most emerging from variations of the amyloid beta peptide, but research has gradually pointed at particular forms, giving drug developers more specific and fruitful targets. A second factor is the improving ability to produce monoclonal anti- bodies that are more effective at hitting their targets.

But what may be the biggest single factor in the breakthrough treatment progress isn’t really about the treatments themselves. Rather, it’s better diagnosis.

A positron emission tomography, or PET, scan, in- volves injecting a radioactive tracer compound into a patient and then scanning for photons emitted. If the tracer binds mostly to something in the body as- sociated with a particular disease, then the scan can be useful in diagnosis. PET scans capable of detect-

have because they included patients who had a differ- ent condition that had little to do with plaque.

Second, PET scan data clearly demonstrated that people with no clinical symptoms sometimes had high levels of plaque, and those people would usu- ally go on to develop symptoms years later. In other words, people with high levels of plaque but no signs of cognitive impairment were simply earlier in the disease progression.

Researchers had long believed that the biological seeds of Alzheimer’s are planted long before—even decades before—cognitive impairment is clearly di- agnosable, but they had no way of knowing which people were on that path. With PET scans closing that gap, drug trials could include patients positively diagnosed, through detection of plaque, while in the earlier stages of the disease, when a plaque-clearing drug might have a better chance of heading off dam- age. What’s more, ongoing PET scans can quickly re- veal whether a trial drug is actually reducing brain plaque, making it easier to focus on drugs that had the best chance of working. Perhaps most important, these scans can reliably identify patients who have the disease in order to know which ones will likely benefit from approved treatments.

All told, the ability to diagnose the disease more surely and earlier, and to track its biological progres- sion, has helped revolutionize the effort to develop and prescribe treatments.

“We don’t have to wait for someone to have symp- toms to know if they have cancer,” says UCSF’s Rabi- novici. “But 100 years after the initial Alzheimer’s case reports, we were still diagnosing by clinical

12 THE NEW AGE OF ALZHEIMER’S

symptoms confirmed at autopsy. These scans repre- sent the modernization of Alzheimer’s care.”

Even better, blood tests are emerging that can pick up biomarkers correlated with the buildup of amyloid plaque in the brain, at much lower cost and higher convenience than a PET scan or a spinal tap, the other way of detecting signs of plaque. Blood tests could eventually become a routine screen for people who are in their 50s, when someone on track to experience cognitive decline from Alzheimer’s in their 70s would probably already have detectable lev- els of plaque.

Hallmarks of Alzheimer’s in the Brain

Established signatures of Alzheimer’s include amyloid plaque, tau tangles, and neuritic-plaque tau. Microglia cause trouble in later disease stages by triggering an inflammatory state that leads to tau buildup, the dying of neurons and cognitive decline.

Amyloid plaque

Better, less expensive and more convenient diag- nostic tests also mean people could more easily get a shot at one of the new plaque-clearing drugs when they may be able to do the most good. Research has shown that patients with mild cognitive decline do better when treated in early stage of the disease. In presymptomatic patients—that is, those who show no cognitive decline, but test positive for plaque— it’s still unproven whether treating them with anti- plaque drugs is effective in slowing or preventing the disease. “It’s an incredibly important question,” says Madhav Thambisetty, chief of the clinical and

Microglia

Neuron

Tau tangles

Neuritic-plaque tau

AXS BIOMEDICAL ANIMATION STUDIO

SCIENTIFIC AMERICAN CUSTOM MEDIA 13

translational neuroscience section at the National Institute on Aging (NIA) and a neurologist at Johns Hopkins University.

Two ongoing phase 3 drug trials intend to answer the question. The AHEAD 3-45 trial is testing the impact of lecanemab on the onset of clinical symp- toms in people who currently have plaque but no symptoms; the TRAILBLAZER-ALZ 3 trial is doing the same with donanemab. Both trials are planned to run through 2027.

get more benefits as research and clinical experi- ence help find ways to match the right drug to the right patients, and to zero in on the optimal doses and timing.

If there is a cloud hanging over the prospects for anti-plaque treatments, it is amyloid-related im- aging abnormalities, or ARIA. ARIA are essentially small bleeds and minor swelling in the brain, first noticed more than a decade ago in MRI scans of pa- tients who were taking some of the first experimen- tal anti-plaque monoclonal antibodies (and also in some patients who were taking placebo). ARIA have continued to show up in a significant portion of pa- tients in trials for these drugs. In most cases there are

Genetic testing, too, will be part of the diagnos- tics picture for Alzheimer’s. Patients can already be tested for the APOE4 gene. About one out of four people have one copy of the gene, which more than doubles the chances of develop-

ing Alzheimer’s, and one in 40 or

so people have two copies, leading

to roughly a 10-fold increase in

risk. Researchers have also found

APOE4 variations that appear to

confer a lower risk of the disease.

Over time, other genetic predispositions or protec- tions from the disease are likely to emerge, and some may also lead to new drug targets and therapies.

Some researchers also point out that the hunt for ever-earlier signs of impending cognitive decline from Alzheimer’s, while a boon to research and ear- ly treatment, requires consideration of privacy and medical ethics issues. Other concerns with genetic and other testing for very early Alzheimer’s include the risk that the results could impact eligibility for employment, life insurance and long-term care.

Attacking the disease

The drug treatments that attack plaque are going to become increasingly effective, insist most research- ers. Now that two anti-plaque drugs have been prov- en to slow the progress of cognitive decline, research- ers and pharmaceutical companies can focus on new, better ways of hitting plaque. That may include new anti-plaque monoclonal antibodies that do a better job. Or it may be pills that work about as well but, un- like most antibodies, don’t need to be ‘infused’ into patients—a biweekly or monthly process in which the drug is slowly dribbled into the body through an in- travenous tube, usually in a clinic setting, or some- times at home with the help of a trained caregiver.

Eli Lilly, for example, is developing a monoclonal antibody called remternetug that in early trials ap- pears effective against plaque and may also be easily injectable under the skin like a flu shot.

Whether through existing anti-plaque drugs or new ones, researchers expect to see more patients

14 THE NEW AGE OF ALZHEIMER’S

“Little by little we’ll approach the point where we can bring the cognitive decline to a full stop.”

no symptoms or only mild ones such as headaches that usually clear up within a few months, but there have sometimes been serious events such as seizures, strokelike symptoms and even death. For that reason, lecanemab carries an FDA “black box” warning, re- served for only drugs with the most serious concerns.

Few researchers suggest that worries over ARIA merit halting the use of anti-plaque drugs, given how welcome the progress in treatment has been to the Alzheimer’s community and how dire the con- sequences of leaving the disease untreated. In addi- tion, clinical trials are conducted on elderly patients with many comorbidities that can obscure the cause of symptoms. Still, many are calling for more re- search. “We have to try to understand the underly- ing mechanisms of ARIA,” says Wilcock. “And we’re in desperate need of biomarkers that would help us identify the patients at highest risk.” Ultimately, she says, it should be possible to identify each individu- al’s chances of being helped by an anti-plaque drug, along with the risk of being harmed, so that doctors, patients and families can make informed decisions about whether taking the drug makes sense. And hopefully drugs to prevent or dampen ARIA will emerge, she adds.

While anti-plaque strategies have been front and center when it comes to finding treatments for Alzheimer’s, another important approach has been gaining more attention recently. It involves going after the so-called tau tangles that spread through the brains of Alzheimer’s patients, particularly in the later stages.

Tau is a type of protein normally found within neurons, or brain cells, helping them to maintain their structure. But in Alzheimer’s disease these pro- teins detach, deform and stick together into tangled forms that ultimately damage the neuron. Although the exact mechanisms of Alzheimer’s remain cloudy, most researchers suspect that the buildup of plaque happens earlier in the disease, and the accumulat- ing plaque eventually accelerates or even causes the formation and spread of tau tangles throughout the brain. Scientists used to think that amyloid and tau were competing theories but now believe they are part of the same disease cascade—that amyloid comes first and lays the groundwork for the forma- tion of tau tangles, which is roughly when symptoms begin to emerge.

Evidence suggests that it is the tau tangles, more than the plaque, that directly cause cognitive de- cline. That theory received a boost from the trial for the experimental anti-plaque drug donanemab. The trial showed that the drug did more to slow cogni- tive decline among patients who had plaque but did

not yet have high levels of tau tangles—patients saw progression of the disease slowed by up to 60 percent. The implication of that finding is that reducing plaque can slow the accumulation of tau, but once tau has sufficiently accumulated reducing plaque alone may be not effective. “We’re already seeing a sequenced approach in drug trials, where first you try to clear out the plaque and then inject an anti- tau drug,” says Gauthier. “I suspect within two years we’ll see an effective anti-tau drug and within three years this will be the normal sequence of treatment

for patients.”

Although plaque and tangles are the main tar-

gets of Alzheimer’s drug development efforts, other factors are known to play a role. Two of the biggest are brain inflammation and brain bleeding from damaged blood vessels. It isn’t known whether these factors become part of the disease, are risk factors for it, or are simply independent factors that exacer- bate and accelerate cognitive decline.

Regardless of their relationship to the disease, re- searchers believe attacking these problems will give Alzheimer’s patients better outcomes. That means ultimately that patients will likely be treated with a combination of drugs.

“In 20 years, we’ll give patients different drugs for plaque and for tangles, and maybe each will slow the decline by 25 percent or more,” says Wilcock. “Then we’ll give them something for inflammation, and maybe that will slow it by another 20 percent. Then we’ll go after the health of their blood vessels and get another 15 percent. Little by little we’ll ap- proach the point where we can bring the cognitive decline to a full stop.”

Disparities

Alzheimer’s puts a tremendous burden on patients, their caregivers and society at large. Patients lose years of productive life. Caregivers often sacrifice income to care for their loved ones who have the dis- ease and their own mental health. All this has a huge impact on the world’s capacity to be productive—a trend that will only increase as populations age.

Medicine may soon be able to help by dramatically slowing or even halting the progression of Alzheimer’s. That raises concerns about how to get treatments to the people who most need them.

One concern is cost. In the U.S., most insurance plans will cover treatments, but deductibles, co- pays and caps will typically leave patients looking at many thousands of dollars in out-of-pocket costs. Only a fraction of the estimated 1 million patients in the U.S. who could qualify for treatments are likely

SCIENTIFIC AMERICAN CUSTOM MEDIA 15

to be able to afford them. In addition, some groups that are more likely to get Alzheimer’s disease, in- cluding Black Americans and Hispanics, also tend to have less access to adequate healthcare and to finan- cial resources for covering out-of-pocket costs.

“This is an incredibly expensive disease,” says Rabinovici, “and we’re seeing disparities for minori- ties in every aspect of it, from inclusion in drug tri- als to access to specialty care. All of us involved in research and clinical care need to think about this and issue a collective call to action.”

The U.S. healthcare system is already struggling with a shortage of clinicians, both primary care and

serves as the vice president of medical and scien- tific relations for the Alzheimer’s Association. That’s because coping with Alzheimer’s will require more than just better treatments for individual patients, Snyder explains. “It’s also going to take public-health actions that can impact behaviors at the population level,” she says.

That means raising awareness of the warning signs of the disease and the need to have a conversa- tion with a physician about them, she says. It also means finding ways to get more people to adopt healthy lifestyles and follow doctors’ advice in order to limit heart disease, obesity, diabetes, and other

“We’re seeing disparities for minorities in every aspect of [Alzheimer’s], from inclusion in drug trials to access to specialty care.”

chronic diseases to help prevent Alzheimer’s. To help, in 2023 the Alzheimer’s Association organized a summit in Atlanta of public-health experts and officials. “We need to en- gage state officials in thinking about how to bring the right risk-reduction messaging to the population,” says

neurologists. That’s leaving many experts worrying how the system will cope with a growing number of Alzheimer’s patients, combined with a new diagnos- tic and treatment protocol that will demand more time and expertise on the part of clinicians. “We’re already scheduling patients six to 12 months out in our memory clinic, and we’re turning many away,” says Jeffrey Burns, a neurologist who co-directs Alz- heimer’s Disease Research Center at the University of Kansas Medical Center. “That’s only going to get worse, especially as we develop ways to treat the dis- ease earlier and earlier on and more patients push for those treatments.”

Burns’s center has pulled together tools that help train clinicians in how to help patients more effec- tively and efficiently and has recruited hundreds of primary care and other doctors and nurses into a support network to provide access to the tools and facilitate information sharing. Those types of sup- ports will help, but Burns recognizes it will be a struggle to scale them up. “The challenges are mag- nified by the fragmented way our healthcare system is structured,” he says. “Different hospitals and prac- tices use different medical-record systems and have their own care protocols.”

The U.S. public-health system, too, is fractured. The Centers for Disease Control and Prevention can issue centralized guidance, but actual public-health policy and programs are developed and implement- ed at the state or even local level. That disconnect will pose another obstacle to managing Alzheimer’s, asserts Heather Snyder, a molecular biologist who

Snyder. “There’s a lot of work to do.” To compound the challenge, preventive medicine has long been a weak point in U.S. healthcare.

Issues of access are even more acute in poor na- tions whose healthcare systems struggle with less challenging diseases. “The kinds of healthcare re- sources we have in higher-income countries like the U.S. aren’t available in many countries around the world, including brain imaging and neurologists,” says Rabinovici. Not all healthcare systems around the world will make new anti-plaque and other Alz- heimer’s drugs available, or cover most of its costs, experts say.

Some pilot programs are addressing various ideas of getting healthcare to Alzheimer’s patients. In Scotland, a pilot program funded by the Davos Alzheimer’s Collaborative (DAC) is beginning to in- clude blood tests and digital-cognitive tests into the regular checkups and national health systems. In Armenia, as part of another DAC-funded program, health workers who go out in vans to administer rou- tine checkups will soon have blood tests and digital assessments.

In spite of these many concerns, the overall feel- ing in the field is that things are finally moving fast in the right direction. “This is an incredibly hopeful and exciting time,” says Wilcock. “For the 24 years I’ve been in the field we’ve been telling patients that treatments were five years away. Now we can finally say we’re here.”

David H. Freedman is a freelance writer.

16 THE NEW AGE OF ALZHEIMER’S

JOEY GUIDONE C/O THEISPOT

Stopping Alzheimer’s Before Symptoms Appear

Scientists are investigating a strategy of “secondary prevention,” in which drugs given early on stave off cognitive decline.

WBY DAVID H. FREEDMAN

hile there are plenty of things that teen- agers wor- ry about, dementia isn’t normally one of them. Yet one new major Alzheimer’s drug trial is recruiting people as young as 18 to answer what may be the most press- ing question facing the field: Can the

ravages of the disease be prevented by identifying those on track to get it and treating them up to 10 years be- fore they show symptoms?

The recent arrival of drugs that slow the cognitive decline of Alzhei- mer’s in many people is a welcome breakthrough, but so far their efficacy has only been demonstrated in people with mild symptoms. By the time patients are diagnosed, their brains have already undergone extensive changes. But growing evidence sug- gests that taking the drugs well be- fore that damage has occurred could

significantly slow the disease and pos- sibly even stop it in its tracks.

“Now we have drugs that can slow the disease by 30 percent or so in

SCIENTIFIC AMERICAN CUSTOM MEDIA 17

people with symptoms, but that’s not good enough,” says Reisa Sperling, a neurologist who heads the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital in Boston. “We want to get to 100 percent, and that means preventing people from getting to the symptomatic stages.”

Earlier and earlier

In medicine, treating a disease when it is causing pathological changes in the body, but hasn’t yet progressed far enough to cause clinical symptoms, is known as secondary prevention. (Primary pre- vention is heading off a disease before there is any pathology, and tertiary prevention is managing symptomatic disease to slow the worsening of symp- toms.) Secondary prevention has been essential to medicine’s triumphs in reducing the risks of death and disability for those with early heart disease or diabetes. Doctors don’t wait for someone to have a heart attack before prescribing a cholesterol-lower- ing statin or for someone to suffer artery or kidney damage before putting them on metformin to con- trol blood sugar.

In 2023, the results of trials of lecanemab (brand name Leqembi) and donanemab on Alzheimer’s pa- tients with mild cognitive impairment suggested that medicine may now have the tools to bring sec- ondary prevention to bear on the disease. Both drugs are monoclonal antibodies that target the hardened clumps of protein called amyloid plaque that form in the brains of Alzheimer’s patients.

Although much is still unknown about the mech- anisms of Alzheimer’s, there is little question now that the buildup of plaque precedes symptoms by many years. In the lecanemab and donanemab tri- als, the earlier patients were along the long road to plaque buildup, the better the drugs did in remov- ing most of the plaque and slowing cognitive decline. “It’s when you remove nearly all the plaque with one of these drugs that you see the real benefits in terms of symptoms,” says Randall Bateman, a physician and professor of neurology at Washington University School of Medicine.

Because patients with even mild symptoms al- ready have a large buildup of plaque, testing the no- tion that plaque-fighting drugs can be more effective earlier in the buildup process means enlisting pre- symptomatic patients for trials. “Studies are moving toward people who are just at the borderline for be- ing positive for plaque and treating them to try to

keep them from accumulating more of it and from having symptoms,” says Susan Abushakra, a physi- cian and researcher who is vice president of clinical

JOEY GUIDONE C/O THEISPOT

18 THE NEW AGE OF ALZHEIMER’S

development and medical affairs at Alzheimer’s-focused biotech company Alzheon in Framing- ham, Mass.

Three past trials have already focused on presymptomatic pa- tients. One was the A4 study run by Brigham and Women’s Sper- ling, which ended in 2020 after six years. It looked at the effect of the anti-plaque drug solanezumab on patients without cognitive impair- ment, but in whom PET imaging revealed some buildup of plaque. The other was the DIAN-TU study, headed by Washington University’s Bateman, which studied the effect of solanezumab or gantenerumab, another anti-plaque drug, on pa-

The A4 and DIAN-TU studies received funding from GHR Foun- dation, which was also involved as lead philanthropic funder in the other trials as well. “Philanthropy can play a distinct catalytic role in this kind of visionary research,” says GHR CEO Amy Goldman. Drug companies may hesitate to plunge into risky trials because shareholders want more certainty; and NIH and other public fund- ing, while substantial, sometimes comes with administrative over- head. Philanthropies can change the game. “We’re willing to take risks and provide the seed money to get a trial started, and we can be patient with long-term, com-

tients with confirmed plaque build- up are underway. One is AHEAD 3-45, also run by Sperling, which will test the effect of lecanemab on patients as young as 55 and as old as 80. The four-year-long trial will actually comprise two sister trials, A3 and A45. A3 is a phase 2 trial that will focus on people with lower levels of brain amyloid, while A45 is a phase 3 trial in which sub- jects have higher levels. In addi- tion, A3 aims to measure the pro- gression in amyloid while A45 will focus more on the onset of cogni- tive impairment. “All the data are pointing in the direction of getting better results by treating patients earlier in the disease, but now we need to prove it,” says Sperling.

Another presymptomatic study is the TRAILBLAZER-ALZ 3, which will test donanemab on subjects with amyloid plaque but no signs of cognitive impairment. One rela- tively unique feature of the trial is that it will try to minimize the inconvenience to subjects, who would normally have to go to se- lect hospitals to have brain scans and periodic in-person cognitive assessments. TRAILBLAZER-ALZ 3, in contrast, will rely primarily on easily administered blood tests and on telephone-based cognitive assessments. Reducing the sub- ject burden in these ways is ex- pected to make it much easier in Alzheimer’s trials to enroll larger numbers of patients and to reduce thedropoutrate.LiketheAHEAD 3-45 trial, TRAILBLAZER-ALZ 3 will run through 2027.

A third study—an additional branch of the DIAN-TU trials—is aiming for a still-earlier interven- tion. That trial will test the effects of lecanemab on 230 subjects as young as 18. Because those pa- tients carry the family genetic mu- tation that makes it almost cer- tain they will develop symptoms of Alzheimer’s by middle age and

“When we first started talking about doing a prevention trial in 2008, people thought we were nuts for wanting to put healthy people in that long a study.”

tients who carry a rare familial genetic mutation that puts them at extreme likelihood of developing Alzheimer’s and starting cognitive decline in their 30s, 40s or 50s.

The third trial was the Alz- heimer’s Prevention Initiative ADAD Trial, which also studied presymptomatic carriers of the familial early-onset mutation. ADAD took place in Colombia, and used the Genentech amyloid- clearing drug crenezumab. The eight-year trial ended in 2021. “When we first started talking about doing a prevention trial in 2008, people thought we were nuts for wanting to put healthy people in that long a study,” recalls Eric Reiman, a physician and neurosci- entist at the University of Arizona and Arizona State University and executive director of the Banner Alzheimer’s Institute, which ran the ADAD study.

plex trials with a high potential for failure, especially with trials like these where there’s also high potential for impact.” Goldman says. Ultimately, the trials are typically funded by public-private philanthropic partnerships.

The three trials failed to find significant benefit to patients. But scientists don’t interpret the find- ings as counter to the idea that anti-amyloid drugs, if given early enough, could potentially pre- vent cognitive decline. The drugs tested in all three trials work by different mechanisms than the newer drugs lecanemab and don- anemab and never reached the same stages of regulatory approv- al. The newer drugs are now re- garded as much more promising. In fact, the DIAN-TU trial is being extended with lecanemab.

Armed with the newer drugs, new trials on presymptomatic pa-

SCIENTIFIC AMERICAN CUSTOM MEDIA 19

most likely by the time they are in their late 30s, the trial provides a chance to see the effects o f t reat- ing the disease two decades or more ahead of the first symptoms.

Technically, this very-early- intervention DIAN-TU trial is addressing primary rather than secondaryprevention,becausethe brains of these young subjects don’t yet show signs of Alzhei- mer’s pathology. But the results are likely to apply to secondary prevention, as well as to patients without the mutation, says Bate- man. “In every study we know of, the results have lined up between people with the mutation and peo- ple with the sporadic form of the disease,” he says, referring to the more common, later-in-life course of Alzheimer’s. “It’s highly likely the results of this trial will inform all of Alzheimer’s.”

Banner’s Reiman is also plan- ning a new ADAD trial using ei- ther lecanemab or donanemab. “Now that those drugs have been studied in amyloid-positive people with mild cognitive impairment, the fact that they work means they’re almost certainly going to work in cognitively unimpaired people,” he contends.

Faster trials, better treatments

One reason that effective A lzhei- mer’s treatments have been so long in coming is that the slow course of the disease, and in particular the long lag between the early buildup of plaque and clinical symptoms, has made drug trials especially slow and costly. Identifying pres- ymptomatic patients with plaque buildup has required PET scans or sampling spinal fluid, and deter- mining whether a drug works on them has required watching them for years for symptoms that can be hard to assess.

But the prospects of drug tri- als on presymptomatic people

may be transforming, experts say. Plaque buildup can now be con- firmed with blood tests, making it much easier and inexpensive to screen potential trial subjects. In a February 2024 paper in Lancet Neurology, Reiman and four col- leagues argued that secondary prevention therapies could be approved for widespread use in three to five years and that blood biomarker tests will be able to be used to determine who is eligible.

In addition to new anti-plaque drugs, a second strategy is picking up momentum in the field: tack-

“These are early days, and we’re still learning a lot. But from everything I know, I think these treatments are likely to work.”

ling the tangles of tau protein that form in the brains of Alzheimer’s patients around the time symp- toms emerge. One theory gain- ing prominence in the field is that the long buildup of plaque eventually triggers or accelerates the formation of tangles, and it is the tangles that primarily cause the emergence and worsening of cognitive decline. Several anti- tau drugs are now in trials. Yet another new arm of the DIAN- TU trial will be testing three of them with Alzheimer’s patients, in some cases combining them with anti-plaque drugs. Sperling, too, is planning a trial where patients will be treated with both anti-am- yloid and anti-tau drugs.

Sperling notes that side effects of the anti-plaque drugs—particu- larly the risk of small-stroke-like

brain bleeds that show up in a small percentage of patients—re- main a concern. So does the cost of treatment, currently running more than $2,000 a month for lec- anemab, plus the cost of adminis- tering the drug intravenously and closely monitoring patients who receiveit.Butshe’sconfidentthe costs will come down—injectable versions of the drug, which are much easier to administer, are al- ready in the works—and that fur- ther research will allow reducing the risks of side effects. “We need to be able to predict and prevent those events,” she says.

Noninvasive therapies are also being developed to preserve brain health. For instance, Cog- nito Therapeutics is developing a headset that uses sensory stimula- tion (light and sound) to provoke gamma-wave activity in the brain, which plays a role in learning and memory and is altered in Alz- heimer’s patients.

Before founding Cognito in 2016, Ed Boyden and Li-Huei Tsai of MIT confirmed in preclinical models that provoking gamma -wave activity with sensory stim- ulation can slow the rate of Alz- heimer’s disease progression. In later phase 2 trials, patients ex- perienced a 69 percent slowing of brain volume loss and a 77 percent slowing of functional decline com- pared to a control group. A recent MRI study of the trial participants suggests that the device’s com- bined visual and auditory stimu- lation reduces white matter atro- phy and myelin loss, which help modulate neuronal network func- tion. (Cognito is funded by in part by Morningside, a sponsor of this special edition, Alzheimer’s Drug Discovery Foundation, X Ventures, and other firms.) The findings sug- gest that nondrug interventions may also play a role in secondary prevention of Alzheimer’s. —DHF

20 THE NEW AGE OF ALZHEIMER’S

“You should know, I’m not a saint.”

Most caregivers of people with Alzheimer’s find themselves behaving in ways they know are counterproductive.

The disease affects their brains, too.

BY DASHA KIPER

| ILLUSTRATIONS BY CARMEN SEGOVIA

Cathy is a woman in her late sixties, with a warm, tremulous voice. For six years, she had been taking care of her husband, Frank, who has Alzheimer’s. Recently, she had begun to berate her- self for not being “cut from the same cloth as Mother Teresa”.

I assured her I didn’t know any caregivers who were, nor did I expect to meet any.

“That’s good,” she said.

“The thing is,” she said, “every day with Frank is the same. He gets up, eats breakfast, reads the pa- per and naps. In the afternoon he grabs the remote, plants himself in his favorite chair, and turns on a game. If it isn’t the Mets, it’s the Jets. If it isn’t the Jets, it’s the Rangers or the Knicks or the Giants. And he’s not a passive spectator. Not Frank. He thinks he’s sitting above the dugout, and when someone fumbles a ground ball or misses a tag, Frank is on his feet, screaming at the poor guy. Or else, he’s leaning forward, predicting loudly when someone will screw up. ‘Don’t do it!’ he’d yell. ‘Wait! Wait!’”

“You should know, I’m not a saint,” she said the first time we met.

SCIENTIFIC AMERICAN CUSTOM MEDIA 21

If it isn’t sports, it’s a movie, any movie—that, too, presents an opportunity for Frank to participate. He yells at the actors, warning them of some impend- ing disaster. Or he forecasts some dire plot twist, shaking his fist at the TV. And if an attractive actress shows up, he might suddenly shout, “That woman is about to take her top off! No one wants to see that!”

For months Cathy had put up with Frank’s behav- ior even though his impromptu yelling and ridicu- lous predictions sucked the joy out of being in the same room with him. But when he became fixated on thieves attempting to break into their house at all hours of the day and night, insisting that she lock the doors and shut all the windows, she had had enough. Her patience and good will had run out.

“No one is out to get you!” she shouted one night. “No one wants anything from you. No one is looking to break in. You hear me? You have dementia! Dementia!”

Cathy knew, of course, that she shouldn’t argue, that it was pointless to use logic and contradict her husband, but she couldn’t help herself.

“I always thought I was a sensitive person,” she mused. “Now I’ve become someone who kicks people when they’re down. I tell him Errol Flynn isn’t going to die. I tell him Doris Day isn’t going to take her blouse off. I tell him he has dementia. Why do I do that?”

Cathy is not alone. The vast majority of caregiv- ers know full well that their spouses or parents are ill, yet they still behave in ways they know are coun- terproductive: arguing, blaming, insisting on reality, and taking symptoms personally. Yes, Cathy under- stood that she was dealing with a disease, with some- one suffering from delusions and hallucinations, but when Frank, panicked by imaginary thieves, refused to crack open a window, Cathy fumed with resent- ment, and that feeling gradually overcame her desire to be understanding and reasonable.

Telling me all this, she shook her head in disbe- lief. “You know, he’s absolutely right. I don’t blame him for getting angry,” she said. “If someone had told me before Frank got Alzheimer’s that my job was to agree with him and accept his reality, I would have said, ‘Sure, what’s so hard about that?’ I mean, who cares that he thinks some jock is going to fall on his ass or that the weather girl is going to flash every- one? It’s not his fault. Who does this?”

“Just about every caregiver I talk to,” I said.

Although Cathy was taken aback by her own ir- rational behavior, it should not surprise us. Reason- ableness is hardly our brain’s first priority. The brain, after all, is an ultrasocial organ that has innate ex- pectations that are often not met when caring for Alzheimer’s patients. So when someone with whom

we’ve had a close relationship develops Alzheimer’s, in many cases he or she begins to retreat into a world where we cannot follow. Not only do patients often not realize they have a neurological illness, they start speaking and behaving in ways that test our own sense of reality.

In Cathy’s case, Frank not only stopped expressing nuance and self-doubt, he also lost his ability to see his wife as a complete person. Cathy had become a prop, a vessel into whom he could pour all of his fixa- tions, and so she found herself living with a humorless stranger with whom she had nothing in common.

It’s one of the heartbreaks of this disease. When someone we love develops cancer, patient and care- giver can commiserate, acknowledging the miseries of the disease while together experiencing, to some degree, a shared reality. But dementia at some point precludes this possibility. This strikes us as pro- foundly unfair because the collective reality that we once shared (and had come to expect) is now gone.

No wonder that unfairness leaves us feeling re- sentful. It’s not because we don’t get our own way, and it’s not really about a shut window or who does the dishes. As social psychologist, Mathew Lieber-

22 THE NEW AGE OF ALZHEIMER’S

man, explains, unfairness actually registers as a loss of social connection, and this feeling of isolation not only doesn’t feel good, it does not bring out the good in us. This is why caregivers invariably bristle when confronted with memory loss, delusions, and loss of judgment. But where outsiders may view this as an irrational reaction to neutral, straightforward symp- toms, caregivers like Cathy experience such symp- toms as relentless reminders that the emotional reci- procity that had once existed between her and Frank had disappeared—and there is nothing remotely fair about that.

Indeed, such unfairness is tantamount to loss. And though we may understand this intellectually, we are biologically disinclined to accept this. This sense of isolation is not a metaphor or a conceit, but a neuro- logical cross that many caregivers must bear. Human beings, after all, are built to experience threats com-

“When someone with whom we’ve had a close relationship develops Alzheimer’s, in many cases he

or she begins to retreat into a world where we cannot follow.”

munally, through what psychologists call load shar- ing. As its name suggests, load sharing is a way of con- serving energy by de-escalating anxiety and stress.

As a result, people in healthy and supportive rela- tionships experience threats less intensely than those who feel isolated or alone. But this doesn’t mean that every close relationship is necessarily beneficial. If, like Cathy, we’re technically not alone but still feel alone, self-regulation becomes effortful, requiring mental energy that isn’t always available. One might think that drawing on such energy with an intact pre- frontal cortex is no great matter. But the right ventro- lateral prefrontal cortex, where our ‘“mental brakes’ ” can be found, is not always able to exercise self-control.

Self-control is, in fact, a limited resource precisely because it’s an effortful activity requiring the same kind of energy that our brain uses for any cognitive, physical or emotional activity, which means that there is precious little of it to go around. Every time caregivers like Cathy try to accommodate a patient’s delusions, they apply mental brakes, which costs energy. Every time they struggle to keep their anger in check, they are hampered by the very people responsible for de- pleting the energy they need to maintain such control.

No wonder that after a long day of submitting to existential and mundane forms of unfairness, caregiv- ers can become as volatile as the people they care for.

Dementia disorders create a physiological ensnare- ment that calls for mental energy even as it makes hitting those mental brakes increasingly difficult. So on top of the heartache and helplessness the disease brings, caregivers are also beset by guilt. They regard their inability to adapt to the disease as a character flaw, and many assume that their difficulties in accept- ing a patient’s hurtful and frustrating symptoms is a matter of moral resolve, a question of will. If only they were “better people,” they tell themselves; if only they were stronger, more capable, more disciplined, they’d be able to handle better what the disease throws at them.

Sometimes the hardest part of listening to care- givers is knowing I can’t assuage this guilt. When caregivers ask me what they can do to help them adapt, my response often surprises them because it has nothing to do with their loved one’s mind, and everything to do with their own. I urge them to in- vest in their own brain, to understand that their be- havior is not a matter of character weakness but a natural outcome of the healthy brain’s limitations.

Most caregivers have only a very rough under- standing of what the disease is doing to their own brains. It’s important to let them know that their own physiology is part of the dynamic, forcing them to dip into those energy reserves required to accom- modate strange and disturbing behaviors. Conse- quently, I urge them to give themselves a break, both figuratively and literally. I encourage them to take vacations, to spend time with friends, to find mean- ing and pleasure with people who can provide the reciprocity that is missing at home. By reducing their own stress, they will become better caregivers.

When I tell caregivers this, many of them nod po- litely but remain unconvinced. And even when they heed my advice and arrange to get away, their guilt rarely dissipates. In fact, self-care feels to them both counterintuitive and selfish. Why should they enjoy themselves when the person they care for has demen- tia and they’re not “there for them.”

Given how inextricably connected our brains are with others, the more compassion and understand- ing we have for our own needs and limitations, the more energy we have to appreciate the needs and limitations of those who depend on us. Self-care is the only way a caregiver’s mind can persevere.

Dasha Kiper is author of the book Travelers to Unimaginable Lands: Stories of Dementia, the Care- giver and the Human Brain (Random House, 2023).

SCIENTIFIC AMERICAN CUSTOM MEDIA 23

The Ten Trillion Dollar Disease

BY DAVID E. BLOOM, SIMIAO CHEN AND ARINDAM NANDI ILLUSTRATIONS BY DAVIDE BONAZZI

Tremendous advancements in science, public health, and material standards of living in recent decades means that people are living longer than ever be- fore. In 1950, when the world’s popu- lation was 2.5 billion, life expectancy at birth was 46.5 years. In 2022, those

figures rose to 8 billion and 71.2 years, respectively. By 2050, global life expectancy is projected to rise to 77.3 years.

This good news, however, presents a challenge: keeping many more older people healthy than ever be- fore. By 2050, the number of people aged 65 and above is expected to reach 1.6 billion, up from 761 million in 2021, according to the U.N.’s World Social Report 2023.

A new model of Alzheimer’s predicts a staggering economic burden and justifies substantial investment in research, testing, treatments and public-health outreach.

Alzheimer’s disease is one of the gravest threats to this growing population: as more and more peo- ple live longer and longer, the total number of people with Alzheimer’s disease worldwide is expected to in- crease by more than 150 percent in the next 30 years. These people have progressively greater challenges in carrying out their day-to-day activities, are more likely to become injured from falls, and face major challenges managing otherwise straightforward med- ical problems. Many people with Alzheimer’s disease suffer from hallucinations, confusion, and depression. It is also an ultimately fatal disease.

Alzheimer’s disease can cause horrible suffering among patients and their caregivers. This suffering is part of the large burden Alzheimer’s imposes on

24 THE NEW AGE OF ALZHEIMER’S

people and their families, public-health systems, and nations. The economic cost of this burden is difficult to assess. It involves not only easily quantifiable ef- fects such as treatment and long-term care costs and loss of work productivity and lifespan, but also myr- iad others that are not easy to measure, such as its effects on the mental health and livelihoods of care- givers and other indirect medical costs.

investments: in R&D spending on Alzheimer’s pre- vention, early detection, and disease-modifying ther- apies; the development of new modalities of care; and widespread, equitable access to these innovations. Experts in public health, medicine and policy are be- ginning to sound the alarm. They warn that massive investments are needed—not just for humanitarian reasons but also as wise economic policy.

The current toll

Disease burden research and estimates have typi- cally focused on dementia, which, in addition to Alzheimer’s disease, also includes vascular demen- tia,frontotemporaldementia,Lewybodydementia, among other forms.

Quantifying the broad economic cost of Alzhei- mer’s disease is important, not least because it is needed to assess the soundness of the expense to bring tests and, eventually, treatments to so many people through health systems. To this end, we have undertaken a comprehensive analysis, drawing on data from the Institute for Health Metrics and Evaluation (IHME), a leading research organization specializing in analyzing the global burden of dis- eases, as well as from other orga-

nizations and prior studies. We

used a methodological approach

that estimates the economic bur-

den of Alzheimer’s disease based

on people’s willingness to pay to

avoid the risk of death. We also

developed a macroeconomic mod-

el of the productive capacity of a

country’s economy that allows for

a reduction in labor and capital

formation resulting from the dis-

ease burden. These methods take

into account a wide array of direct

and indirect costs of Alzheimer’s disease for individ- ual patients, caregivers, and the aggregate economy.

Based on our willingness-to-pay approach, we estimate that the global economic burden of the dis- ease in 2019 was roughly $2 trillion. By 2050, that burden will rise sharply to about $10 trillion and perhaps as high as $13.5 trillion. For comparison, world GDP is projected to be $228 trillion (inflation adjusted) in 2050.

The problem is especially urgent because the eco- nomic burden of Alzheimer’s is projected to worsen global economic inequality. Although the current economic costs of Alzheimer’s are concentrated in the wealthiest countries, these will grow much fast- er in low- and middle-income countries, which are less able to shoulder them. Between now and 2050, the number of people with Alzheimer’s disease in Northern Africa, the Middle East, and Eastern Sub- Saharan Africa is projected to grow by 250 percent, compared to 150 percent worldwide.

The economic burden of Alzheimer’s disease will be staggering and justifies a substantial scale-up of

Dementia is the sixth-leading source of disability burden among those aged 55 and older. Alzheimer’s disease accounts for approximately 60 to 80 percent of this burden. Based on this proportion, estimates from IHME suggest that in 2019, 34 million to 46 million people around the world had Alzheimer’s. Even if the age- and sex-specific prevalence of dementia remains stable in the coming years, popu- lation growth and rising longev- ity mean more people will be at risk of Alzheimer’s disease. In this vein, the total number of people living with Alzheimer’s disease is projected to rise to about 107 million by 2050. (For this estimate and some others in this article, we give the midpoints of projected ranges; in this case, the

range was between 91 million and 122 million.) Despite decades of research, medical interven- tions that substantially prevent, slow the progression of, or cure Alzheimer’s disease are not yet available. While there are many successful models of coordi- nated care for people with Alzheimer’s disease, they are not widely implemented. Most face difficult deci- sions about trying to receive care at home or living in a nursing home, both marked by hospitalizations

and visits to the doctor.

A traditional method for tabulating these ex-

penses is the cost-of-illness (COI) approach, which includes out-of-pocket medical and long-term care expenditures for patients and costs incurred by such payers as insurance companies or government-run healthcare systems. Globally, an estimated $184 bil- lion was spent in direct healthcare costs for people with Alzheimer’s disease in 2019. By 2050, that num- ber is projected to reach $1.1 trillion per year. While

“By 2050,

the burden of Alzheimer’s disease will roughly grow fivefold to $10 trillion and perhaps as high as $13.5 trillion.”

SCIENTIFIC AMERICAN CUSTOM MEDIA 25

high-income countries are expected to see direct costs from Alzheimer’s disease multiply by a factor of five during this time, upper-middle income, low- er-middle income, and low-income countries could see these COI estimates grow by factors of 21, 15, and 13, respectively.

A 2018 study using the cost-of-illness approach estimated the combined direct and indirect global costs of Alzheimer’s, including costs associated with seeking medical care (such as transportation and meals), the value of lost economic productivity of pa- tients and caregivers, the medical cost of treating de- mentia-induced events (such as injuries) and, finally, the cost of the mental suffering of caregivers. The authors estimated the combined direct and indirect global costs of Alzheimer’s disease to be between $575 billion and $766 billion in 2015 and projected that it would increase to about $6.4 trillion by 2050.

COI studies, however, have limitations. Most leave out what economists call “productive

nonmarket activities,” which include

caring for grandchildren, volunteer-

portunity cost (potential earnings of the caregiver if they were instead gainfully employed in the market), and others have calculated replacement cost (the economic value of an equivalent amount of care that could be given by a professional caregiver at home instead of the unpaid caregiver). For a person with dementia in the U.S., these indirect cost estimates range from 31 to 49 percent of the total cost of care.

Even considering the lost market productivity of informal caregivers, other factors contribute sub- stantially to the total cost of Alzheimer’s. Caring for people living with the disease is mentally and emotionally difficult for family members, but this pernicious impact is an indirect cost that is typically overlooked. Seeing your parent, grandparent or other loved one suffering from a debilitating disease like Alzheimer’s can be heartbreaking. The caregiver is often a witness to changes to their loved one’s per- sonality and a deterioration of their memories—a

ing in the community, and other

unpaid activities that enrich lives.

These activities are not measured

traditionally in terms of wages or

economic output and are rarely included in conven- tional estimates. In the U.S., 46 percent of a person’s total lifetime economic output is estimated to come after the age of 60—about half of it from employ- ment, half from unpaid activities. Because of lack of data, analyses of the cost of care for Alzheimer’s dis- ease, even if they include formal productivity losses for patients and caregivers, typically do not capture these nonmarket activities.

The economic costs of Alzheimer’s disease go even further beyond the cost of treatment or long- term care, as we and our colleagues reported in npj Aging in February 2024. A patient may no longer be physically or mentally capable of being employed or be less productive at work, both of which can re- duce their own earnings and, in turn, the aggregate economic output of a country. Moreover, in many communities, especially among low-income families that cannot aff ord expensive nursing homes or home visits by professional caregivers, unpaid caregiving by family members (especially women) remains the norm, likely exacerbating income inequality. In fact, as many as 94 percent of people with dementia in low- and middle-income countries such as Brazil, China and Costa Rica receive their care at home. To quantify the lost economic productivity of unpaid caregivers, some researchers have calculated op-

decline that often leads to the inability to recognize family members. A comprehensive assessment of the economic burden of Alzheimer’s would include the toll on caregivers and other indirect costs.

A different way of looking at costs

Another method for measuring the potential eco- nomic burden of Alzheimer’s is called the value-per- statistical-life, or VSL. The VSL measures a society’s willingness to pay for lowering the risk of death. If a representative person were willing to pay $100 on average for a 1 in 100,000 reduction in the probabil- ity of one’s own death, it would take $10 million paid by 100,000 such individuals to collectively avoid one death (or to save one “statistical life”). VSL reflects how individuals value their own lives, presumably encompassing various aspects of healthy living that may range from having a job and earning money to being physically and mentally active, enjoying a good book, a vacation, or spending time with loved ones.

The VSL approach to assessing the economic bur- den of Alzheimer’s typically delivers estimates that encompass a broader range of value than estimates based on macroeconomic modeling or human capi- tal and cost-of-illness approaches. But VSL-based estimates—like estimates based on these other meth- ods—are subject to criticism.

“The problem of Alzheimer’s threatens to significantly worsen economic inequality.”

26 THE NEW AGE OF ALZHEIMER’S

ury disease

Stroke ’s disease

Diabetes Suicide

Lower respiratory disease Neonatal conditions

Diabetes Suicide

Alzheimer’s disease Diarrheal diseases

Diabetes Kidney disease

Injury Lower respiratory disease Stroke

Alzheimer’s disease Diabetes

Ten Leading Causes of Death

Heart disease Cancer

Heart disease Stroke

U.S.

Pulmonary disease Lower respiratory disease

World

U.S. W

125

150 125 100 75 50 Deaths per 100,00

*2019 is the most recent year global data are available. In 2020, COVID wa

Sources: J. Xu et al., National Vital Statistics Reports, Vol.70, No.8 (2021); “The top 10 causes o

175

50 Deaths per 100,000 people 50 75 100

are available. In 2020, COVID was the third-leading cause of death in the U.S.

Vol.70, No.8 (2021); “The top 10 causes of death,” World Health Organization, December 9, 2020.

100

Kidney disease a and pneumonia

150 125 100

75 50

ace

hat has

60%

2018)

6.7 million people living with

Age

Alzheimer’s Disparities by Race

Alzhe

In part t But one have ne Alzheim

Additio AD in w

AD in m

Source: “Race

Diabetes

’

B–u8t4one study found that at each age, other dementias

have nearly the same prevalence in both genders, yet

Additional AD in women

Alzheimer’s appears more in women.

A8d5d+itional AD in women

AD in men

0% 20%

a diagnosis

ODtehmerendteiampernetvialsence

Source: C. Beam et al., Journal of Alzheimer’s Disease, 64, 1077 (2018)

20% 40% 60%

Dementia prevalence

Source: C. Beam et al., Journal of Alzheimer’s Disease, 64, 1077 (2018)

70 80 90

Age of onset

Source: “Race, Ethnicity, and Alzheimer’s,” Alzheimer’s Association Fact Sheet, March 2020.

Injury

Lower respiratory disease Heart disease

Ten Leading Causes of Death

Stroke Pulmonary disease Alzheimer’s disease

Heart disease Cancer

Trachea, bronchus, lung cancers Alzheimer’s disease

Stroke

Neonatal conditions

Trachea, bronchus, lung cancers

40%

85+70

Kidney disease Influenza and pneumonia

Sources: J. Xu et al., National Vital Statistics Reports, Vol.70, No.8 (2021); “The top 10 causes of death,” World Health Organization, December 9, 2020.

Alzheimer’s Disparities by Race and Ethnicity in the U.S.

Alzheimer’s Disparities by Gender

65–74

Alzheimer’s Disparities by Gender

In the U.S., two-thirds of the

Whites

Alzheimer’s disease are women.

Blacks

and Ethnicity in the U.S.

Estimated 2.5% likelihood that

the person has

a diagnosis

90 100

In the U.S., two-thirds of the

In part the difference exists because women live longer. But one study found that at each age, other dementias haAvegenearlythesameprevalenceinbothgenders,yet

Hispanics

6.7 million people living with

Whites

Estimated

65–74

Blacks Hispanics

Other dementias

Age of onset

likelihood that

Onset rate

the person has

125

175

Onset rate 2.5%

60%

100

AD in men

U.S. World

Suicide Kidney disease Kid*2n0e1y9disistehaesmeost recent year global data are available. In 2020, COVID was the third-leading cause of death in the U.SI.nfluenza and pneumonia

Diarrheal diseases

Deaths per 100,000 people

’

In part the difference exists because women live longer.

Alzheimer’s appears more in women.

75–84

SCIENTIFIC AMERICAN CUSTOM MEDIA 27

[ INFOGRAPHIC ]

The Ballooning Economic Impact of Dementia

New models predict that the cost of Alzheimer’s and other dementias will grow sixfold by 2050.

As dementia skyrockets worldwide, so too will the costs to governments, healthcare systems, and economies. In 2022, David E. Bloom of Harvard and colleagues from the U.S., Canada and Germany published a study that modeled those costs to 2050. They considered the lost value of a statistical life—an economic metric that estimates what the public is willing to pay to reduce risk—for patients with dementia and projected that value forward in time as world populations grow and age. By mid- century, the financial burden of dementia will increase sixfold and shift from high-income countries to upper-middle-income ones. —Katie Peek

Northern Eurasia $580 billion

North America $1.7 trillion

Western Europe $2.2 trillion

China and Taiwan $2.7 trillion

2019 $2.8 trillion High-income countries $2.3 trillion

East Asia $380 billion

Western Europe $640 billion

East Asia $770 billion

Western Europe $1.2 trillion

Upper-middle-income countries $470 billion

Lower-middle-income countries

$54 billion

Lower-income countries $0.65 billion

North America $1.4 trillion

East Asia $930 billion

North America $470 billion

China and Taiwan $860 billion

North America $1.0 trillion

o n

Western Europe $1.7 trillion

28 THE NEW AGE OF ALZHEIMER’S

China and Taiwan $8.7 trillion

South Asia $660 billion

KEY

Northern Eurasia $880 billion

o n t r i l l i $ 1 7 5 0 2 0

Each circle represents the total economic burden—in 2020 U.S. dollars—of the years lost to Alzheimer’s and other types of dementia. The area of each segment represents the dollar value lost. Thick lines separate different income levels; segments within those areas are colored by world region. (The smaller areas are approximated.) Regions correspond to the colors in the map below.

Source: A. Nandi et al., eClinicalMedicine, September 2022, Vol.51:101580

One common criticism is that VSL-derived cost estimates increase with income, suggesting that the lives of people living with Alzheimer’s disease in rel- atively high-income countries are worth more than the lives of people living with Alzheimer’s disease in low- or middle-income countries. This ethically prob- lematic property of the VSL approach arises from the fact that VSL is derived from people’s willingness to pay for relatively small reductions in mortality, which in turn reflects their ability to pay.

This criticism can be addressed in multiple ways, such as by assuming that the value-per-statistical-life year (VSLY)—calculated as VSL divided by the ex- pected number of years of life remaining—is the same for all countries. Modifications like this, however, are atypical in the literature on this topic. To keep our estimates broadly comparable to those of other econ- omists, we chose not to make this adjustment to the VSL estimates in the study reported in this article.

Another criticism of the VSL approach is that it does not include all costs of Alzheimer’s disease, such as those associated with informal caregiving, medi- cal research, or medical care paid for by third parties. This issue can, however, be addressed by interpreting VSL estimates as underestimates of the true costs or by separately calculating the excluded cost compo- nents and adding them to the VSL figures.

In a recently published study in eClinicalMedi- cine, we adopted the VSL approach to estimate the economic burden of Alzheimer’s disease and other forms of dementia across 168 countries containing more than 99 percent of the world’s population.

In this study, we obtained data on disability ad- justed life years (DALYs) lost to Alzheimer’s disease from a database prepared by the IHME Global Bur- den of Diseases study. A DALY represents the loss of the equivalent of one full year of healthy life. DALYs are calculated as the sum of the years of life lost for those who die from Alzheimer’s and the effective years of life lost for those who experience disability from the disease. The more severe the dementia, the more effective years of life are lost. For example, one year of living with severe Alzheimer’s is equivalent to 0.6 year of living without the disease, and one year of living with mild disease is equal to 0.93 year of living without it.

We then monetized each DALY lost to Alzhei- mer’s disease as being equal to VSLY. For instance, to calculate the VSLY for the U.S., we started by consid- ering the VSL for the U.S., which various U.S. govern- ment agencies and researchers have estimated to be approximately $10 million to $12 million. (For other countries, VSL is typically derived by adjusting the

SCIENTIFIC AMERICAN CUSTOM MEDIA 29

U.S. estimate for differences in income and purchas- ing power.) Based on standard life table estimates, a median-aged U.S. resident in 2019 would have a re- maining life expectancy of 43 years. The VSLY figure for the U.S. comes to $246,512 ($10.6 million divided by 43 years). This figure represents the monetary value of each year of full health lost to Alzheimer’s in the U.S., which can be interpreted to include the value ofallmeasurableaspectsofahealthyyearoflife,such as employment, as well as intangible aspects, such as enjoying leisure. It likely does not capture the full eco- nomic value of unpaid caregiving, which constitutes a large part of overall care costs for Alzheimer’s.

method and VSL method—can reliably estimate the economic impact of Alzheimer’s disease on people with the disease and their caregivers, neither account for its longer-term and aggregate macroeconomic ef- fects. Deaths and disability from Alzheimer’s disease diminish the size and productivity of the workforce, reducing national economic output.

Out-of-pocket care costs from Alzheimer’s dis- ease can significantly deplete household savings. These savings might otherwise have been invested in retirement accounts or used to support family busi- nesses or the education of children or grandchildren. Costs incurred by health insurance companies trans-

We projected future VSLY values

for each country based on average

annual growth rates of gross na-

tional income per capita from 2010

to 2019. Based on these figures and

our projections of Alzheimer’s cas-

es (which assume that Alzheimer’s

would continue to account for 60 to

80 percent of the future global bur-

den of dementia, we estimate the global economic burden of Alzheimer’s disease in 2019 to be about $2 trillion. We also project that the global economic burden of Alzheimer’s would rise to between $2.8 trillion and $3.8 trillion in 2030, to between $5.1 tril- lion and $6.8 trillion in 2040, and to between $10.1 trillion and $13.5 trillion by 2050. These estimates are reported in 2020 U.S. dollars, with future values discounted at the rate of 3 percent per year.

Our findings also show that the global center of gravity of the economic burden of Alzheimer’s will gradually shift away from high-income countries, which currently have the greatest number of people with Alzheimer’s and toward upper-middle-income countries, which will experience rapid growth in the number of older adults and, as a result, those living with Alzheimer’s. Between 2019 and 2050, the VSL- based economic burden is projected to increase by a factor of 22 in upper-middle-income countries, as compared to 3 in high-income countries. The burden will also grow in other parts of the world at greater rates than in high-income countries, though their absolute magnitude in 2050 will remain low in com- parison with upper-middle-income countries.

While the two approaches for assessing the eco- nomic burden that we’ve discussed thus far—the COI

“Good health confers follow-on economic and social benefits that need to be acknowledged and appropriately valued.”

late to higher insurance premiums and lower house- hold savings for consumers. Similarly, costs paid by social healthcare systems may need to be funded by taxes that, in turn, reduce personal savings. Finally, diverting money to Alzheimer’s care might reduce vi- tal public investments in education, other aspects of health, and infrastructure development that gener- ally have high economic returns.

Our macroeconomic model

To account for the effects of Alzheimer’s disease on national and global economies, we developed a mac- roeconomic model that simulates the productive ca- pacity of a country’s overall economy. It accounts for the reductions in labor from Alzheimer’s-related mor- tality and morbidity, both for patients and caregivers, and reductions in capital formation because of lower savings. It iteratively estimates the value of economic output based on the available labor and capital stock, part of which is then saved by households and invest- ed as capital to spur future economic production.

We estimated that during the 2020-2030 decade, loss of labor and lower rates of capital formation would lead to a global macroeconomic cost of $1.5 tril- lion. We project cumulative losses between 2020 and 2040 to be about $4.3 trillion and losses from 2020

30 THE NEW AGE OF ALZHEIMER’S

to 2050 to be about $7.3 trillion. These estimates are conservative, however, in that they do not account for likely economy-wide technological progress, and they do not include the value of productive nonmarket ac- tivities of people with Alzheimer’s disease.

Macroeconomic analyses provide a fundamen- tally different view from COI or VSL on the potential future economic burden of Alzheimer’s disease. All take into account demographic and disease-burden patterns, but macroeconomic analyses also account for the underlying rates of household savings, capital formation, and average income in each country. Our macroeconomic analyses find that while low- and middle-income countries are projected to bear the largest health burdens—close to three-quarters of the DALYs lost to Alzheimer’s disease by 2050—their share of the macroeconomic burden would remain just under 50 percent. As another example, South Asia would still account for 19.4 percent of the DALYs lost to Alzheimer’s in 2050 but only 1.6 percent of the macroeconomic burden from 2020 to 2050, while North America would account for only 4.5 percent of the DALYs in 2050 but 28.5 percent of the economic loss from 2020 to 2050.

Like our willingness-to-pay (VSL) analysis, our macroeconomic burden modeling uses underlying disease-burden projections that differ from the latest IHME estimates. Our projections assume that the Alzheimer’s disease burden would continue to grow in each country at the same rate as in the past (from 2010 to 2019). By contrast, IHME’s estimates are based on a more detailed methodology that consid- ers several contributing or risk factors for dementia, such as education level, physical activity, and expo- sure to air pollution. However, the IHME estimates are available only for 2050 and not the intermedi- ate years that we evaluated. The IHME study also does not directly report the DALYs that are used in our analyses. Our linear projections of future Alzhei- mer’s cases are slightly lower than IHME estimates: 133 percent between 2019 and 2050 versus 166 per- cent in IHME estimates. This suggests that our esti- mates of the economic burden of Alzheimer’s disease may be relatively conservative. While our estimates may be limited by some uncertainty surrounding the future disease burden, they nonetheless present a strong economic case for investing in research to prevent and manage Alzheimer’s disease.

To be sure, recent research has shown that wealth and health are a two-way street. Population health is a benefit of affluence, and healthy populations tend to have more vibrant and robust economies than their less healthy counterparts. Healthy populations also tend to be more stable, cohesive, equitable, and secure. Insofar as global societal well-being is driven by population health in a plethora of ways, the full benefits of population health need to be acknowl- edged and measured in the interest of efficiently al- locating scarce public and private resources and gar- nering the biggest returns from them.

The combination of a rapidly aging global popu- lation and the lack of treatments for Alzheimer’s is problematic now. In the coming decades, as the toll of the disease swells rapidly, it could become a sig- nificant impediment to human progress. In 2020, the U.N. General Assembly declared this decade as the Decade of Healthy Aging, calling upon governments, civil society organizations, the private sector, aca- demic experts, and other stakeholders to join hands in improving the lives of older adults. It would be wise to act now.

David E. Bloom is Clarence James Gamble Profes- sor of Economics and Demography at the Harvard T.H. Chan School of Public Health. Simiao Chen is an associate professor and head of research unit at Heidelberg Institute of Global Health at Heidelberg University. Arindam Nandi is a researcher at the Population Council. The following individuals are also coauthors: Zhong Cao (Tsinghua University), Nathaniel Counts (NYC Department of Health

and Mental Hygiene), Maddalena Ferranna (USC Alfred E. Mann School of Pharmacy), Benjamin Seligman (UCLA David Geffen School of Medicine), Daniel Tortorice (College of the Holy Cross), and Daniel Vigo (University of British Columbia Dept. of Psychiatry and School of Population and Public Health). The Davos Alzheimer’s Collaborative pro- vided financial support, through a contract with Data for Decisions, LLC, for our original research described in this article.

The authors are grateful to Joseph Dieleman for constructive comments on a previous version of this article.

SCIENTIFIC AMERICAN CUSTOM MEDIA 31

A Marathon Journey from Lab to Clinic

How 20 years of molecular detective work led to the first effective Alzheimer’s drugs.

BY ESTHER LANDHUIS

32 THE NEW AGE OF ALZHEIMER’S

On a spring day in 2011, neuro- scientist Cynthia Lemere stood nervously before scientists gath- ered to appraise the world’s lat- est research—including hers—at a conference on immune strategies for treating Alzheimer’s disease.

Advancing her presentation slides to show stained brain tissue from a recent set of mouse experiments, Lemere circled the pointer around the reddish-brown clumps: protein fragments called amyloid beta that form plaques, a hallmark of the disease. In Lemere’s experiments, mice that received antibody treatment accumulated fewer amyloid plaques than animals re- ceiving placebo.

Some in the audience were skeptical. As Leme- re recalls, when she finished her presentation one prominent researcher rose and proclaimed: “It’s not a real thing. It’s a biochemical artifact.”

What that researcher dismissed, others pursued. Lemere and colleagues at Brigham and Women’s Hospital in Boston have studied this form of amyloid beta since the 1990s; so have researchers in Japan and Germany. Now, the rogue pro-

and accessible, as well as new training to equip phy- sicians to recognize early-stage disease and decide who is eligible for treatment.

Molecular underpinnings

Alzheimer’s is the most common cause of dementia. It afflicts nearly 7 million people in the United States and more than 30 million worldwide. Older drugs—

tein is center stage: A drug (don- anemab) that targets the molecule recently showed clear benefits in a large clinical study of people with mild Alzheimer’s disease.

“Watching a neurodegenerative disease cause the slow decline of a loved one is sad, worrisome and exhausting”

including donepezil, galantamine and rivastigmine—work by pro- longing the activity of key chemi- cal messengers in the brain. This enhancement of nerve cell com- munication offers a temporary boost but does not get at the dis- ease’s molecular roots.

The newest drugs do. They are the long-awaited fruit of the amyloid hypothesis, the theory that identifies amyloid buildup as an essential trigger that disrupts

Donanemab’s success follows

another Alzheimer’s drug, lec-

anemab (brand name Leqembi),

which hit the market in January,

and aducanumab (brand name

Aduhelm), which got a nod from

the U.S. Food and Drug Adminis-

tration in 2021 after a controversial review. These are the first new Alzheimer’s treatments since 2003, and the only ones to impede the disease’s progression; earlier drugs only eased symptoms.

neural circuits, causing mental decline and other signs of dementia decades later. This theory has driven much of the Alzheimer’s disease research and drug development since the 1990s.

Creating drugs to slow this progression requires a deep understanding of how the culprit molecules form and how they become a threat. Before amyloid clumps into disease-associated plaques, it floats in the blood as harmless proteins. Day by day, decade af- ter decade, these amyloid beta peptides are churned

2000 B.C. Egyptians note that people started to lose their memory as they grew older.

The new therapies are revitalizing Alzheimer’s research and renewing hope for millions of families touched by this devastating disease. Yet these treat- ments carry some risk and a formidable price tag. Translating them from controlled studies to clinical use will require diagnostics that are more scalable

A Brief History of Alzheimer’s Disease

Dementia has been around for eons, but scientists distinguished Alzheimer’s from other forms only in the last 100 years or so. Now effective treatments and tests are in development.

Sources: Phyllis Barkman Ferrell; ”Milestones” by the Alzheimer’s Association, https://www.alz.org/alzheimers-dementia/research_progress/milestones.

SCIENTIFIC AMERICAN CUSTOM MEDIA 33

out and cleared out, like scores of other proteins pro- cessed in the brain as part of normal metabolism.

At some point, though, things go awry. Amyloid collects and forms clumps in the brain, eventually killing nerve cells and making it hard for people to remember things and manage everyday tasks such as paying bills and getting dressed. “Watching a neurodegenerative disease cause

tures called fibrils, or as intermediate-sized oligomers, which many researchers consider to be the most tox- ic to nerve cells. Plaques can act as a reservoir for these smaller, toxic species.

What’s more, individual peptides differ in length and shape and sometimes morph further through chemical reactions, as shown in scores of biochemical

the slow decline of a loved one is sad, worrisome and exhausting,” says Lemere. She lost two aunts to a related condition, Lewy body dementia, and says that “definite- ly had an impact on my desire to keep working in this field.”

“Creating drugs to slow the disease’s progression requires a deep understanding of how the culprit molecules form and how they become a threat.”

To study the progression of Alzheimer’s, Leme- re and colleagues use laboratory mice that are en- gineered to mimic key pathological manifestations of the human disease. One example: the plaques stained reddish-brown on Lemere’s conference pre- sentation slides.

Each clump represents amyloid beta, but these peptides are anything but identical. Some exist alone as monomers. Others assemble into menacing struc-

1906 Alois Alzheimer, a German psychiatrist and neuropathologist, first describes “a peculiar disease” in the case of Auguste D., a patient who had profound memory loss, unfounded suspicions about her family, and other worsening psychological changes. In her brain at autopsy, he saw dramatic shrinkage and abnormal deposits in and around nerve cells.

studies. One variant—a ring-shaped molecule called pyroglutamate amyloid beta (pyroglu Aß) is especial- ly nasty. In lab studies decades ago, it seemed sturdi- er and stickier than other amyloid peptides and hurt nerve cells even at tiny concentrations.

These observations were later confirmed in thera- peutics tested on mice and ultimately in clinical tri- als of Alzheimer’s patients—but it has taken decades to capture attention from the scientific community.

An intriguing culprit

Initial descriptions of pyroglu Aß appeared in the biomedical literature as early as 1985. Interest grew as multiple labs published follow-up papers confirm- ing the presence of this unusual protein in autop- sy tissue from Alzheimer’s patients. In some brain specimens Lemere analyzed in the 1990s as a Ph.D. student, pyroglu Aß appeared as a dominant species.

In those analyses—when Lemere noticed that py- roGlu showed up well in some samples but less so in others—it seemed to depend on how the tissues were processed. When specimens sat in fixative solution for longer than a few hours, pyroglu Aß was faint or undetectable, she says.

Methodological challenges like that plagued the field for years, fueling claims that pyroglu Aß was a biochemical artifact.

There was another problem with pyroglu Aß: No one could explain how it was formed. Then, in 2000, a doctoral student in Germany studying diabetes made a surprising discovery. Stephan Schilling was investigating how a pancreatic hormone resists deg- radation in the bloodstream.

Sources: Tangle visualization: P. Liu et al., Signal Transduction and Targeted Therapy 4, 29 (2019); Robert Katzman: S. Pincock, The Lancet 372, 1804 (2008) (oppostie page)

34 THE NEW AGE OF ALZHEIMER’S

He found that the hormone was chemically al- tered by an enzyme that adds pyroglutamate and that the same enzyme can add pyroglutamate to many other proteins—including amyloid beta.

During his postdoc, Schilling reported in 2008 that inhibiting this enzyme, called glutaminyl cy- clase, curbs amyloid buildup and improves cogni- tion in mice and fruit flies that model Alzheimer’s disease.

An inhibitor of the enzyme has been developed by Vivoryon Therapeutics AG, a German precision med- icine company, and is now being tested in a study of people with mild Alzheimer’s disease, says Schil- ling, who is now a professor at Anhalt University of Applied Sciences and serves on Vivoryon’s scientific advisory board.

While developing the enzyme inhibitor, company researchers started pursuing another strategy—im- munizing mice with antibodies against pyroglu Aß. The rationale was that if pyroglu Aß is found in

1963 Pathologists Robert Terry and Michael Kidd visualize tangles in the Alzheimer’s brain using electron microscopy.

1968 Researchers develop the first validated clinical rating scale for assessing cognitive and functional decline in older adults.

plaques, then targeting it with antibodies could low- er brain amyloid and slow cognitive decline. Schilling and Lemere joined forces in 2008, testing pyroglu Aß antibodies made by Probiodrug AG, which later became Vivoryon, on Lemere’s brain tissue samples and Alzheimer’s mouse models.

Amyloid immunotherapy

By then, amyloid had emerged as a prime focus for Alzheimer’s drug development. The first strategy to reach clinical testing was active immunotherapy: vaccinate with amyloid beta peptide to stimulate an immune response to remove amyloid deposits.

This approach worked in mice and was further studied in people with mild to moderate Alzheimer’s disease. But investigators stopped that trial in 2001 after 6 percent of participants developed brain in- flammation, presumably resulting from an autoim- mune response to injection with a naturally occur- ring protein.

1976 Neurologist Robert Katzman alerts doctors that dementia is not a normal part of aging, and that Alzheimer’s is its most common cause, in an Archives of Neurology editorial.

1974 Congress establishes the National Institute on Aging (NIA) as one of the National Institutes of Health (NIH). It becomes the primary federal agency supporting Alzheimer’s research.

First clinical rating scale: S. Tomaszewski Farias, Neuropsychology 22, 531 (2008)

SCIENTIFIC AMERICAN CUSTOM MEDIA 35

[ INFOGRAPHIC ] Alzheimer’s Impact on the Brain

The latest neuroscience tracks where the disease begins and how it progresses.

Alzheimer’s disease impairs a patient by destroying neurons, which otherwise live for decades, and by disrupting communication among the remaining brain cells. As neurons die, the areas of the brain they constitute begin to atrophy. A detailed picture of the progression is still under inves- tigation, and the disease follows different tracks in different patients, but researchers have found brains afflicted with Alz- heimer’s typically atrophy along the same basic pattern. A better understanding of that pattern may provide the foundation for methods to diagnose the disease earlier, which in turn would give medication and lifestyle changes the best chance of slowing de- mentia. In broad strokes, here’s how Alzheimer’s tends to change a brain. —KP

Regions of the Brain Most Affected

Cerebral cortex

Made of gray matter and located in the outermost layer of the brain, this wrinkled tissue contains more than 10 billion neurons and is responsible for advanced thinking and processing. It’s divided into four major areas, which occur in pairs across the left and right hemispheres. Each region has a distinct specialty in mental functioning, and each has a distinct vulnerability to Alzheimer’s.

Occipital Lobes A

Function: The occipital lobes mainly process input from the eyes. They recognize colors and shapes, integrate depth perception, and pass the resulting images on to the rest of the brain.

The Progression of Alzheimer’s Disease

The clinical hallmarks of Alzheimer’s include the proteins amyloid beta and tau, as well as neurological degeneration as neurons die. Here’s the typical progression in time.

1. Preclinical

Before memory loss begins,

the brain, bloodstream and cerebrospinal fluid begin to accumulate amyloid beta and tau. The buildup happens either because the brain (shown here in a front cutaway view) is mak- ing too much of the proteins or because the body isn’t clearing them fast enough. Alzheimer’s begins after neurons start dy- ing, with degeneration visible on a brain scan.

healthy brain

early degeneration

JOLYGON/

ISTOCK

36 THE NEW AGE OF ALZHEIMER’S

With Alzheimer’s: Confusion, vision loss, and even hallucinations can happen as the area deteriorates, but the occipital lobes are affected relatively late in the typical progression of the disease.

Temporal Lobes B

Function: Conscious memories are stored in the temporal lobes. That includes both events in

a person’s past and general knowledge such

as facts, meanings of words, and concepts.

With Alzheimer’s: Atrophy in the temporal lobes happens early in Alzheimer’s progression, which is why memory loss is often an early symptom. In late-stage Alzheimer’s, temporal lobes can shrink considerably.

Parietal Lobes C

Function: The parietal lobes compile sensory

inputs to deduce the body’s position in space

and allow a person to recognize environments.

The region is also responsible for reading and writing.

With Alzheimer’s: Parietal lobes experience significant atrophy, which can create difficulty with reading and writing. It also disrupts telling left from right; identifying objects by touch; and getting dressed and performing other complex spatial tasks.

tau

amyloid plaque

2. Early stage

As the disease progresses, amyloid beta begins to form plaques in the brain areas between the neurons.

Tau proteins within neurons build up into so-called neurofibrillary tangles. Neurons continue to die, especially in the hippocampus, amygdala and temporal lobes.

Frontal Lobes D Function: Decision-making, impulse control, and other more advanced cerebral tasks happen in the frontal lobes.

With Alzheimer’s: Frontal lobes atrophy relatively late in the disease, but when they do, attention, task-switching, and appropriate social behavior are all affected.

Subcortical structures

A collection of smaller components that collectively make up about 25 percent of the brain’s volume, the subcortical structures are involved in both higher and lower thinking. Collectively, they act as an information hub for the brain while also governing emotional regulation, motivation and movement control.

Amygdala

Function: Emotional processing happens in this almond-shaped structure, nestled between the hippocampus and the frontal lobes. It activates fear responses and links memories with emotion.

With Alzheimer’s: The amygdala begins to atrophy early in the progression of Alzheimer’s. The effects of that atrophy are still being studied, but there’s evidence that it leads to agitation and aggression.

Thalamus

Function: Shaped like a small egg, the thalamus is a critical hub for information in the brain. It relays sensory inputs

to the higher-level gray matter (the cerebral cortex), while also governing wakefulness and attention.

With Alzheimer’s: Imaging and post- mortem studies of patients with advanced Alzheimer’s tend to show atrophy in this region.

3. Late stage

After years or even decades, a brain with Alzheimer’s will have significant amyloid plaque buildup and visible atrophy in other brain regions, including the parietal lobes.

Hippocampus

Function: A pair of seahorse-shaped structures deep in the brain, the hippo- campi are a control center for information, making sense of input and forming new memories.

With Alzheimer’s: The hippocampus is one of the first regions affected as Alzheimer’s takes hold. Because it’s involved with memory retrieval—and with more recent memories in particular—atrophy of the hippocampus explains why newer memories might fade but older memories persist.

SCIENTIFIC AMERICAN CUSTOM MEDIA 37

To avoid those harmful effects, some Alzheimer’s trials turned to passive immunotherapy—injecting antibodies directly into the patient rather than stim- ulating the patient’s body to make them.

Scientists at Lilly Research Laboratories in In- dianapolis developed an antibody that binds solu- ble amyloid beta, thinking this

could shift the equilibrium to

failed in a large phase 3 trial; Johnson & Johnson and Pfizer decided in 2012 to discontinue this drug. Although the drugs failed to help patients, the two studies did mark the first use in Alzheimer’s re- search of an important new tool: positron emission tomography (PET) brain scans that measure amyloid load in the brains of live patients. PET revealed that nearly a quarter of participants in the solanezum- ab and bapineuzumab trials did not in fact have Alzheimer’s—their scans showed no brain amyloid— so the tested drugs could not have helped them. And though the Alz- heimer’s antibody trials were fail- ing to identify new drugs, collec- tively the trials were teaching researchers something valuable: experimental treatments seem to work bet-

ter when started earlier in the disease process.

Soon Eli Lilly took another shot: It enrolled 2,129 patients in an 18-month trial, in which they would

prevent neurotoxic aggregates

from forming. The antibody

looked impressive in Alzheimer’s

mice, reversing memory defi-

cits even as amyloid piled up in

their brains. But when Eli Lilly

created a humanized version of

this antibody and moved it into

clinical trials, the antibody, solanezumab, failed to help patients with mild to moderate symptoms who enrolled in two late-stage, placebo-controlled stud- ies. Meanwhile, bapineuzumab, an antibody that recognizes both soluble and plaque amyloid, also

1984 The NIA establishes a network of Alzheimer’s Disease Centers at leading medical institutions to promote research, diagnosis and treatment.

1986 Scientists identify the tau protein as

a key component of tangles—the second characteristic feature of Alzheimer’s disease and another leading suspect in nerve cell degeneration.

1987 The NIA and Warner-Lambert Pharmaceutical Company (now Pfizer) launch the first Alzheimer’s drug trial of tacrine (now Cognex), which succeeded.

1984 Researchers George Glenner and Cai’ne Wong identify amyloid beta as the primary component of Alzheimer’s brain plaques and a likely trigger for nerve cell damage.

1993 The first gene known to raise the risk of Alzheimer’s is identi- fied. People with the gene—APOE4—do not necessarily develop the disease.

THE NEW AGE OF ALZHEIMER’S

“It’s important to try to find ways to mitigate ARIA. Before I retire, I have to figure this out.”

1993 Tacrine (Cognex) becomes the first FDA- approved drug specifically target- ing Alzheimer’s thinking and memory symptoms. Over the next decade, four additional drugs are approved.

receive monthly infusions of either the drug solan- ezumab or a placebo. To qualify for that study, par- ticipants had to test positive for amyloid, by brain scan or spinal fluid analysis. Yet even with the tight- ened criteria, the company reported in late 2016 that treated patients showed only a hint of improvement, relative to the placebo group. “It did move the needle, but not enough to be a medicine,” says Eric Siemers, who started a consulting business in 2017 after 19 years directing Eli Lilly’s Alzheimer’s disease pro- gram. “That was a big disappointment.”

And although passive immunotherapy has proved safer by avoiding the brain inflammation that halted the 2001 active immunotherapy trial, antibody infu- sions still raise concern. A subset of participants de- velop brain swelling and microbleeds—amyloid-related imaging abnormalities (ARIA), which show up on mag- netic resonance imaging (MRI) scans. Some patients experience symptoms—typically headache, confusion or nausea—and three participants in clinical trials with ARIA have died, so patients with ARIA symptoms must

1994 Former U.S. President Ronald Reagan shares that he has been diagnosed with Alzheimer’s disease.

1995 Scientists develop the first transgenic mouse model for Alzheimer’s by inserting the gene for a human amyloid precursor protein that’s linked to a rare, inherited form of Alzheimer’s disease.

be monitored. But most ARIA cases are asymptomatic, transient and resolve with corticosteroids.

Despair and determination

Alzheimer’s drug development is high stakes and high risk. More than 300 interventions—79 of them amyloid-related—have entered clinical testing, and 99 percent of experimental therapies have performed no better than placebo in clinical trials, according to the therapeutics database at Alzforum, a web re- source for researchers studying Alzheimer’s and re- lated disorders.

Given these tough odds, companies hedge their bets. While testing antibodies, some also pursued other amyloid strategies—for example, a pill that re- duces amyloid beta levels by blocking the activity of an enzyme called BACE1 that is required to produce it. “A lot of people were convinced that these BACE in- hibitors were going to be the solution,” Siemers says.

But four large studies of such drugs showed no drug-placebo difference in Alzheimer’s patients; in

1999 The first “Alz- heimer’s vaccine”— injections of amyloid beta—prevents trans- genic “Alzheimer mice” from developing plaques and other brain changes typical of the disease.

2003 To identify additional Alzheimer’s risk genes, the NIA launches the National Alzheimer’s Disease Genetics Study to collect blood samples from families prone to late-onset Alzheimer’s.

2005 The Healthy Brain Initiative is launched by the CDC and the Alzheimer’s Association with the publica- tion of A National Public Health Road Map to Main- taining Cognitive Health.

S N

CH3 NH

2004 A new imaging agent, Pittsburgh Compound B (PIB), promises progress in disease monitoring and early detection. PIB enters the brain through the blood- stream and attaches to amyloid beta deposits, where it can be detected by posi- tron emission tomography (PET) scans.

SCIENTIFIC AMERICAN CUSTOM MEDIA 39

fact, treated participants actually got a bit worse. For

New hope

some researchers, the failed trial of Merck’s BACE in-

That was a “turning point,” says Knopman, whose hibitor in 2019 was a breaking point. It prompted a

enthusiasm for amyloid-lowering treatments had reevaluation in the field. “To be blunt, amyloid-beta

waned with past failures of BACE inhibitors and im- lowering seems to be an ineffective approach, and it

munotherapy trials. More success followed. In 2022 is time to focus on other targets to move therapeutics

Eisai and Biogen reported that participants with ear- for Alzheimer’s disease forward,” Mayo Clinic neurol-

ly-stage Alzheimer’s who were treated with another ogist David Knopman wrote in a 2019 commentary

amyloid antibody, lecanemab (Leqembi), declined 27 shortly after the failed trial.

percent more slowly than the placebo group in a large For Schilling, such declarations instilled determi-

18-month trial. And in summer 2023, Eli Lilly reported

nation to continue the research. “I wanted to show

that donanemab slowed cognitive worsening by 35 per- all these people that [pyroglu Aß] is a concept that is

cent in amyloid-positive mild Alzheimer’s patients who viable and that can be used to develop a treatment,”

also had low to moderate levels of another protein, tau. he says. Meanwhile, Lemere’s team used the pyroglu

The latest results suggest that patients lose func- Aß antibody developed by Schilling’s Probiodrug col-

tion five months later than they would have other- leagues to treat Alzheimer’s in mice. Reporting in a

wise during 18 months of treatment, according to a February 2012 paper, “we found that we were clearing

recent analysis by researchers at Pentara, a clinical regular amyloid beta as well,” she says.

trials consulting firm. This could preserve their abil- A team from Eli Lilly published similar findings

ity to drive or delay their need to move into a nursing

with their pyroglu Aß antibody later that year and

home, says CEO Suzanne Hendrix, a statistician who ultimately advanced it into clinical testing before

helped Eisai design a key scoring metric for the piv- the smaller Probiodrug team could. In spring 2021,

otal trial leading to lecanemab’s FDA approval.

the company reported that this drug, donanemab,

As the newest Alzheimer’s drugs begin the chal- slowed cognitive decline in a phase 2 trial of 257 par-

lenging transition from research trials to real-world ticipants with early Alzheimer’s disease.

use, researchers are testing new types of therapies

biomarker magnitude

2012 The FDA approves Amyvid, the first imaging agent to reveal amyloid plaques in brain scans of living people, suggesting that PET

scans can be used to diagnose

the disease.

2012 Researchers from Iceland report first gene mutation that protects against Alzheimer’s. Icelanders with this mutation

are five times as likely to reach

85 without developing the disease. The work points to amyloid beta as a therapeutic target.

2013 The largest-ever Alzheimer’s gene study, the International Genomics of Alzheimer’s Project identified 11

new genetic variations that increase the risk of Alzheimer’s disease, including some that seem to confirm the immune system’s key role in the disease.

abnormal

2010 Researchers publish a working model relating changes in Alzheimer’s biomarkers to disease stage and symptom severity.

The model has since become a focal point of research into Alzheimer’s biomarkers, and is revised periodically to account for new research.

normal

clinical disease stage

2010 Data released by the Centers for Disease Control and Prevention (CDC) National Center for Health Statistics show that Alzheimer’s disease has become the sixth leading cause of death in the U.S.

40 THE NEW AGE OF ALZHEIMER’S

“If my amyloid beta and tau are high, maybe I get on a drug that can lower those and prevent me from getting Alzheimer’s, and in someone else it might be a different brain protein. These panels are going to tell us what is going on in the brain and what we might be at risk for developing over time.”

that they hope can achieve stronger benefits with fewer side effects.

Eli Lilly itself is working on a newer pyrogluta- mate antibody that eases some of donanemab’s side effects and seems to clear plaques faster, according to early data reported this spring. And researchers at Vivoryon, working with Schilling and Lemere, are try- ing to re-engineer their pyroglu Aß antibody so it can- not activate the immune reactions underlying ARIA.

“It’s important to try to find ways to mitigate ARIA,” says Lemere. “Before I retire, I have to figure this out.” Meanwhile, several companies are still pursuing active immunotherapy by creating safer amyloid beta vaccines that could one day be deployed to prevent disease, especially once blood tests replace the much

costlier brain scans to detect preclinical Alzheimer’s. In another decade or so, some researchers think such blood panels could become routine—and they would check not just amyloid and tau but also other proteins that are associated with dementia or neurode- generation. Screening would start around age 65 or 70. “If my amyloid beta and tau are high, maybe I get on a drug that can lower those and prevent me from get- ting Alzheimer’s, and in someone else it might be a dif- ferent brain protein,” says neurologist Gil Rabinovici, who directs the Alzheimer’s Disease Research Center at the University of California, San Francisco. “These panels are going to tell us what is going on in the brain and what we might be at risk for developing over time.”

Esther Landhuis is a science journalist who has written for Nature, Medscape, Undark, Quanta, Science News, NPR and others. She holds a Ph.D in immunology from Harvard University.

IMAGES: ALZHEIMER’S BIOMARKERS: C. JACK ET AL., THE LANCET NEUROLOGY, 9, 119 (2010); LARGEST ALZHEIMER’S GENE STUDY: J-C. LAMBERT ET AL., NATURE GENETICS, 45, 1452 (2013) (PRECEDING PAGE)

2014 “I’ll Be Me,” a documentary by James Keach, follows country singer Glen Campbell on his last tour as he struggles with Alzheimer’s. By opening up about the disease, Campbell and his family began to ease its stigma.

2019 Annual NIH funding for Alzhei- mer’s and dementia research in the U.S. receives a $350 million increase and reaches $2.8 billion, an all-time high.

2017 A historic $400 million increase in U.S. federal Alzheimer’s disease research funding is signed into law, bringing annual allotment to $1.4 billion.

2023 Lecanemab (Leqembi) receives FDA approval for the treatment of early Alzheimer’s disease with confirmation of elevated amyloid beta. This is the first traditional approval of an Alzheimer’s treatment that changes the underlying course of the disease.

2021 Aducanumab (Aduhelm) received accelerated approval as the first FDA- approved Alzheimer’s therapy.

2023 Donanemab is found to be at least as effective as the newly approved drug lecanemab (Leqembi).

Donanemab effectiveness: “The Alzheimer’s Treatment Landscape: Leqembi vs. Donanemab,” by Heather McKenzie, BioSpace, September 2023.

SCIENTIFIC AMERICAN CUSTOM MEDIA 41

42 THE NEW AGE OF ALZHEIMER’S

An Alzheimer’s Test for Everyone

In just a few years, annual checkups may include a blood test that screens for Alzheimer’s, ushering in a new era of preventive medicine.

HBY SUZANNE SCHINDLER | ILLUSTRATION BY HAROL BUSTOS

enry, a carpenter in his late 50s who stress, sleep apnea, various medical conditions, and worked for a small business, had certain medications.

been making and refinishing furni- When patients with subtle changes in memory and ture for years. Then he started hav- thinking come to our clinic and the cause is unclear, a ing difficulty using tools. The qual- common strategy has been “cognitive monitoring”— ity of his work rapidly declined, and watching patients over time to see if their problems eventually he was fired. At home, get better, stay the same, or get worse. Some patients

his wife grew frustrated with him for forgetting their improve after interventions such as stopping a medi- conversations. He was not doing a good job with cation or starting treatment for sleep apnea. Some

chores such as loading and unloading the dishwasher. Henry went to see a doctor, who referred him for cognitive testing. The results came back “invalid.”

patients continue to experience cognitive difficulties but never really worsen. And some patients progres- sively decline until it becomes clear that they have

Among the potential diagnoses the neuropsychologist came up with was “malingering”—basically faking his cognitive impairment. The specialist apparently did not anticipate that someone so young might have dementia. As a result, Henry’s application for disability benefits was denied.

Given the need for rapid diagnosis of Alzheimer’s, I expect that blood tests will become the dominant approach to testing.

a neurological disorder. Which leads to another difficult question: Are their symptoms caused by Alz- heimer’s disease?

Clinicians define dementia as a decline in memory and thinking that affects a patient’s function in everyday activities. There is a con- tinuum of dementia, from being unnoticeable by people who do not know the patient well to caus- ing complete dependence on oth- ers for dressing, bathing, eating,

By the time Henry walked into

my clinic at Washington Univer-

sity in St. Louis, he and his fam-

ily were confused and desperate.

His wife thought perhaps Henry was being lazy and didn’t want to work or help around the house. But he seemed to struggle with simple tasks, such as dress- ing himself, and his problems were getting worse. She was worried.

toileting and other simple tasks. Dementia, particu- larly when very mild, can have many causes, some of which are treatable. Alzheimer’s is the most common cause of dementia in patients older than 65 years. It is characterized by specific brain changes, includ- ing the deposition of amyloid plaques. These brain changes slowly worsen over time and can be detected 10 to 20 years before the onset of symptoms.

Not long ago, it was impossible to know for sure whether a patient with cognitive impairment had Alzheimer’s disease or some other cause of dementia without an autopsy. In recent years we have vastly improved our diagnostic capabilities. We can now offer blood tests that can enable earlier and more accurate diagnoses of large numbers of people.

As a cognitive neurologist, many patients come to see me because they’ve noticed subtle changes in their memory and thinking. Their major ques- tion is, “Do my symptoms represent the beginning of a progressive neurological illness like Alzheimer’s disease?” The answer is often not clear at their first visit, even after I take a detailed history, do brain imaging, and check routine blood work. Mild prob- lems with memory and thinking are relatively com- mon and can have many causes, such as poor sleep,

SCIENTIFIC AMERICAN CUSTOM MEDIA 43

Spinal taps and amyloid PET scans

The era of Alzheimer’s treatments

In 2012, the U.S. Food and Drug Administration

On July 6, 2023, a treatment for Alzheimer’s disease that attacks an underlying cause of disease was fully approved amyloid PET scans, which can reveal the

approved by the FDA. This treatment, lecanemab, presence of the amyloid plaques characteristic of

Alzheimer’s disease and which are thought to initi-

works by clearing amyloid plaques from the brain of patients with mild symptoms of Alzheimer’s and ate a cascade of brain changes that culminate in de-

slows the progressive cognitive decline. A similar mentia. In 2022, the FDA approved the first t est f or

Alzheimer’s disease that measured amyloid proteins

treatment, donanemab, has done well in clinical tri- als. While we need even better treatments, we are fi- in the cerebrospinal fluid or CSF.

nally starting to make progress against Alzheimer’s. For more than a decade, neurologists like me had

been using CSF tests to determine whether patients

And there are now nearly 150 treatments being stud- ied in clinical trials.

with cognitive impairment were likely to have Alz-

heimer’s brain changes. While neurologists perform

Now that there are specific treatments, testing for spinal taps to collect CSF to test for a variety of con-

Alzheimer’s needs to be done in many more patients, not just the occasional patient like Henry. These ditions, and it is safe and well-tolerated, most people

have never had a spinal tap and it may seem scary.

treatments are likely to be most effective if given to Even if the CSF testing provides a more certain di-

patients early in the disease, when symptoms are mild. Cognitive monitoring for a year or two isn’t rea- agnosis, patients often aren’t interested in having a

spinal tap unless it has a major impact on their care.

sonable now that there may be “something we can do Patients will ask, “If I test positive, is there anything

you would do differently?” For years, in most cases I have said, “Probably not,” and that I would still treat them with the same medications and follow them in the same way. For this reason, we didn’t do many tests for Alzheimer’s—as my patients put it, “There’s nothing we can do about it anyway.”

There were some exceptions. I did CSF testing on Henry, the carpenter who could no longer build furniture or load the dishwasher. It was positive for Alzheimer’s disease. As I had suspected, Henry had an atypical form of Alzheimer’s that affects brain cir- cuits involved in visual-spatial functioning—exactly the ones Henry needed in his work. With a clear diagnosis, Henry was able to get disability benefits, and his wife understood that his issues were caused by a brain disease.

Amyloid PET scans are another technique that can be used to detect and quantify the amyloid plaques characteristic of Alzheimer’s. The patient is injected with a very small amount of a radioac- tive tracer that binds amyloid plaques in the brain. Positron emission tomography (PET) is a sophis- ticated imaging technique that can take pictures of this radioactivity and visualize the distribution of amyloid plaques in the brain. An amyloid PET scan, however, costs around $6,000 in my medical

system. There are also not that many PET scan-

ners. The largest study of amyloid PET, called the

IDEAS study, performed 20,000 scans over about 18 months in sites all over the U.S. That’s a lot of scans, but the number of people who might need testing for Alzheimer’s could be in the hundreds of thousands or even millions.

Positron emission tomography (PET) imaging can now detect the presence of amyloid plaque in the brain, a sign of Alzheimer’s disease. The brain on the right has plaque, while the one on the left does not.

44 THE NEW AGE OF ALZHEIMER’S

about it”. However, relatively few patients with mild cognitive concerns visit a neurologist and undergo a comprehensive dementia evaluation that includes amyloid PET and CSF testing, and many patients are not diagnosed with Alzheimer’s dementia until the disease has progressed beyond the point that new treatments may be helpful. Now that a treatment is available that is most effective early in the disease, there is a sense of urgency to the diagnosis of Alz- heimer’s disease.

SCIENCE PHOTO LIBRARY

AND INFORMATICS INSTITUTE /

MARK AND MARY STEVENS NEUROIMAGING

About three years ago, our memory clinic per- formed about five spinal taps a month. Now that lecanemab is available, we have scaled up and are now performing about 30 spinal taps per month. It’s difficult to do many more, because the procedure is very time-consuming. We spend about 10 to 15 min- utes talking about the procedure and getting con- sent, which is necessary because most patients have never had a spinal tap and some are anxious about it.

Blood tests for Alzheimer’s

Blood tests are the critical tool needed to enable large-scale testing that may allow for more rapid di- agnosis of Alzheimer’s and initiation of treatments when they are most effective. Unlike CSF testing and amyloid PET scans, blood tests are already a routine part of healthcare. When I see a patient with memory and thinking problems, I send them for routine blood work that includes blood counts, blood chemistries,

Blood biomarker tests may supplant CSF and amyloid PET testing, for individuals who suspect they may have Alzheimer’s disease, within the next three years.

a vitamin B-12 level, and thyroid function studies. However, in pa- tients coming to see me because of cognitive concerns, these routine studies are much less informative than an Alzheimer’s blood test would be.

Since 2017, researchers have made remarkably rapid progress in developing blood tests for Alz- heimer’s. Some of these blood tests

The procedure takes about 20 minutes. Afterwards a small number of patients have issues such as back pain or headache, which may require additional fol- low-up. Amyloid PET scans can be costly, even when insurance covers them, so we haven’t been ordering them very often. Both amyloid PET and CSF tests are highly accurate for detecting the brain changes of Alzheimer’s, but they are too expensive and cumber- some to be used for every person suspected of having Alzheimer’s.

are now available in the clinic, and many more are on the way. The tests generally measure a handful of different proteins that are strongly associated with Alzheimer’s brain changes. Levels of these proteins can help clinicians decide whether a patient’s cogni- tive symptoms are likely to be caused by Alzheimer’s. Blood tests are also now being used by clinical trials to identify older, cognitively normal individuals with early Alzheimer’s brain changes who are at high risk of developing dementia.

The first blood test for Alzheimer’s was developed in the laboratory of Randall Bateman at Washington University and became available for clinical use in December 2020. It measured the ratio of two forms of amyloid in the blood and determined a person’s forms of apolipoprotein E, which is a major risk fac- tor for Alzheimer’s. More recently, Nicolas Barthele- my, working in Bateman’s laboratory, developed an even better test that measures specific tau proteins in the blood. A version of this tau blood test com- bined with the amyloid test is now being used in our clinic for select patients. Although studies are still underway and the test is not yet FDA-approved, ini- tial results suggest that this tau blood test has simi- lar or even higher accuracy than CSF tests.

Recognizing that blood tests for Alzheimer’s are critically needed, many other researchers and compa- nies have been working to develop their own. There are now at least 16 Alzheimer’s blood tests in various stages of development. Some tests, like Barthelemy’s, are highly accurate while other tests perform quite poorly. Somewhat surprisingly, the requirements to market a test to patients are low, leading to the avail-

SCIENTIFIC AMERICAN CUSTOM MEDIA 45

ability of Alzheimer’s tests in the clinic that are not well validated and would result in the misdiagnosis of many patients.

How accurate does an Alzheimer’s blood test need to be? Even amyloid PET and CSF tests, while strongly associated with Alzheimer’s brain changes, aren’t perfect. Is it acceptable to misdiagnose one in four patients? (I certainly

don’t think so.) Is it accept-

able to misdiagnose one in

10 patients, or one in 20?

Does it make a difference if

the misdiagnosed patient is

actually on the borderline

of having early Alzheimer’s

brain changes?

than the occasional patient like Henry. Broad-based blood testing is the only way that we will be able to identify most individuals with very early symptoms of the disease. Although these Alzheimer’s blood tests are currently used almost exclusively by cogni- tive neurologists like me, as the tests are better vali- dated and clinicians learn more about them, they

After returning the re-

sults of Alzheimer’s tests

to many patients over the

past decade, my conclusion

is that tests used in clini-

cal diagnosis need to be

highly accurate. A diagno-

sis of Alzheimer’s disease

changes the way patients

see themselves and their fu-

ture; the information guid-

ing this diagnosis must be correct. Accuracy is espe- cially important if patients are going to be started on an Alzheimer’s-disease-specific treatment based on this test result.

After much discussion with colleagues, we gener- ally agree that blood tests used in clinical diagnosis need to be on par with FDA-approved CSF tests or we probably would not use them and ideally would correctly classify 90 to 95 percent of patients. Some of the newest blood tests meet this high threshold, especially because they can categorize individuals as positive, negative, and intermediate. Identify- ing individuals in this intermediate category, who have borderline levels of Alzheimer’s brain changes, allows much greater confidence i n t he p ositive a nd negative results. Individuals with intermediate re- sults can be re-tested in a year or assessed with an- other type of test.

Given the greatly increased need for more rapid diagnosis of Alzheimer’s, and the major limitations of spinal taps and amyloid PET, I expect that blood tests will become the dominant approach to testing for Alzheimer’s disease brain changes within a few years. Because blood collection is so accessible, use of Alzheimer’s blood tests would enable us to test most patients presenting for cognitive concerns, rather

There is a clear public- health benefit for making blood biomarker tests

as accurate as possible— so that fewer people would have to be referred for additional, expensive testing.

will certainly enter into primary care settings. This is largely because there are so many older adults and so few cognitive neurologists.

In another couple of years, there may be another transformation. Clinical tri- als are now underway to test whether certain treat- ments, when used in cog- nitively normal individu- als with Alzheimer’s brain changes, can prevent or slow the onset of dementia. If those trials are successful and demonstrate that we can stave off Alzheimer’s dementia, we could enter a time where primary care

clinicians screen cognitively normal older individu- als at annual visits with blood tests to see wheth- er they have Alzheimer’s brain changes. This may herald an era when Alzheimer’s disease becomes a chronic medical management issue, like high cho- lesterol, rather than the devastating illness that we know today.

Suzanne Schindler is a clinical neurologist and neuroscientist focused on improving the diagnosis and treatment of Alzheimer’s disease. She completed the M.D./Ph.D. program and trained in neurol-

ogy at Washington University. She currently sees patients with memory concerns and coordinates biomarker testing for the Washington University Memory Diagnostic Center. She leads the Fluid Biomarker Core for the Knight Alzheimer Disease Research Center.

Disclosures: Schindler served on a Scientific Advisory Board for Eisai. Washington University has an in- terest in C2N Diagnostics, a company that offers an Alzheimer’s blood test. She does not have any financial interest in C2N Diagnostics or any other pharmaceuti- cal or diagnostic companies. Some details about Henry, including his name, have been modified to protect his confidentiality.

46 THE NEW AGE OF ALZHEIMER’S

[ INFOGRAPHIC ]

How to Detect Alzheimer’s Before Symptoms Appear

New technologies for catching the disease in the early stages are critical

for slowing the progression of the disease—and perhaps one day forestalling it entirely.

The best time to treat Alzheimer’s is early, but it’s a stealthy thief. By the time symptoms of cognitive decline become apparent, the disease has been slowly and invisibly changing the brain for as much as 20 years.

PET scans and tests of cerebrospinal fluid can reveal the biomarkers of this early activity, but to screen large populations, doctors need less expensive and less invasive methods. Scientists are now developing a range of technologies for early detection. No single test is expected to solve the problem—it will probably take a con- stellation of different screenings. “This is a complex disorder,” says Mark Roithmayr, head of the Alzheimer’s Drug Discovery Foundation. “Let’s embrace the complexity and bring in a multifactorial approach.” Here are some of the most promising ones. —KP

DROP: BLACKJACK3D/ISTOCK; EYE: DRAGANAB/ISTOCK; CHROMOSOME: JIAN FAN/ISTOCK; PHONE: NATALYABUROVA/ISTOCK.

Blood-based

Alzheimer’s is a disease of the nervous system, but it triggers complex changes in the body that sometimes turn up in the blood. Successful screenings may combine measurements of many dif- ferent factors, such as levels of tau and amyloid beta, brain inflammation, and proteins, called neurofilaments, released when the brain begins to atrophy.

Genetic

The genetic causes of Alzheimer’s may be too complex to serve as as diagnos- tics. But the DNA in mitrochondria— organelles that appear in almost every cell in the body—show lower numbers and more mutations in patients with Alzheimer’s. Tests under development might detect such changes before clinical symptoms emerge.

Ocular

A visit to the eye doctor may soon include a screening for Alzheimer’s. Early stages of the disease cause changes in the brain that ripple out through the nervous system to the optic nerve. Scientists can now detect them with retina scans, and several firms are developing commercial technologies. (For more, see page 51.)

Digital

Smartphones and fitness trackers have an intimate view of their owner’s sleep patterns, cognition and motor function. A team at Boston University is developing an algorithm that detects dementia based on a 10-minute questionnaire, which anyone can take for free and which allows patients to track their results over time to look for signs of decline.

Early Dementia

Symptoms

Important areas that testing strategies are targeting:

Memory loss, especially difficulty with recently learned information and asking the same question repeatedly

Concentration problems, such as difficulty following a recipe or making decisions

Language difficulty. For example: upon trying to recall a name,

the person draws a blank—as opposed to remembering the first letter or number of syllables in a name, which is considered normal forgetfulness

Perception trouble, especially with recognizing objects, judging dis- tances and interpreting patterns— for example, mistaking a friend’s identity

Location and time confusion, for example, leaving on an errand and forgetting how to get home again

Mood shifts, including rising levels of anxiety, irritability and apathy

SCIENTIFIC AMERICAN CUSTOM MEDIA 47

Many primary

(Diagnostic tools, by contrast, are used to establish the presence care doctors

of the disease, usually by detect- have had a

complicated

ing amyloid.) Many of these new screening tools use artificial-intel- relationship

ligence algorithms and can be ad- with tests

designed to

ministered by medical assistants without extensive training. They screen their patients for Alzhei-

hold out the promise of inexpen- mer’s disease. Beyond recommend-

ing a few lifestyle changes—tweaks

sive and noninvasive methods of to diet, exercise and sleep most

screening people for Alzheimer’s. would recommend anyway—there

“Dementia is the number-one was little they could do to help pa-

fear of people over 55,” says David tients with a confirmed diagnosis.

Bates, CEO of Boston-based Linus As new drugs expand the op-

Health, a digital assessment com- tions for treating and preventing

pany. “You have drug companies Alzheimer’s, demand from older

that are about to be advertising people worried about their mental

their drugs. And you’re going to fitness and seeking routine screen-

have commercials and marketing ing for Alzheimer’s and other de-

stoking that fear to drive people mentia is expected to rise quickly.

to ask for the drug. So you’re going In anticipation, several commer-

to have this onslaught of demand cial firms are racing to bring to

in the health system. Primary care market new digital screening tools

doctors will not be able to meet that can detect warning signs that

that demand. They’re going to get the disease could be developing.

overwhelmed.”

PET imaging and tests of ce- rebrospinal fluid, which docu- ment the presence of amyloid beta plaques in the brain, are cur- rently the gold standard for pro- viding a diagnosis of Alzheimer’s. But these tests are too expensive and cumbersome to administer to meet the anticipated need for Alz-heimer’s screening in large populations. Although blood tests that can flag the buildup of am- yloid are beginning to emerge from the lab, they are not yet widely available.

For years, primary care physi- cians have instead relied on pen- and-paper cognitive tests to screen patients with mild cognitive im- pairment, but these tests can take 20 to 30 minutes to complete and require a trained administrator. The “reality is primary care doc- tors don’t have that time,” says Brad O’Connor, CEO of CogState in Australia.

IMAGES COURTESY OF LINUS HEALTH

48 THE NEW AGE OF ALZHEIMER’S

Beyond Pen and Paper

Digital cognitive tests designed to spot early signs of Alzheimer’s are beginning to hit the market.

BY ADAM PIORE

A test sold by Linus Health combines an established pen- and-paper test based on a simple drawing test with added artificial intelligence to make it easier to administer and more powerfully analytic. In the test, a patient is asked to draw a clock with the clock hands indicating a specific time. The task engages disparate areas of the brain involved in mo- tor, visual, analytical and other functions that are often impaired by dementia.

In the original version of the test, the patient draws the clock on a piece of paper, and a trained observer evaluates the results and refers the patient on for further testing. Linus’s version, originally developed at MIT and commer- cialized by a company called Digi- tal Cognition Technologies that

clinics and longitudinal epidemio- logical studies, including both the Framingham Heart Study and a Rush Hospital study documenting the health of primarily minority populations.

In a study, scientists from Linus and Harvard Medical School found that they could detect signs of cognitive dysfunction in less than three minutes in patients who didn’t previously report impair- ment. The scientists checked each detection with PET scans, which

“The reality is primary care doctors don’t have that time” to administer paper- and-pencil tests.

Health System, at UMass Medical School, at Emory University and in about 50 small medical practices. It has so far been used on several thousand patients.

“We are not suggesting that this is the only cognitive assess- ment you should ever do, but it’s a really low-cost, noninvasive, easy assessment that will identify those first changes and get people at least on the pathway for assess- ment of the issues—and also con- versely conclude this person is not at risk to decline in the next five years. Which really helps doctors with the ‘worried well,’ because they’re fine, but they take up a lot of healthcare resources.”

Several other firms are work- ing on digital tests aimed at ad- dressing this growing demand.

CogState plans to roll out Cog- nigram, in the U.S. early next year. It uses a virtual deck of playing cards, which can be displayed on a computer screen, to assess mem- ory and cognition. The company has partnered with the Japanese drug maker Eisai, the makers of Leqembi, to get it into the hands of doctors.

CogState is perhaps best known for computer-based cognitive as- sessments designed to measure changes in cognitive function over time. Its Cogstate Brief Battery test, which is widely used in clini- cal trials, healthcare and academ- ic institutions, uses the digital cards to establish a baseline in ar- eas such as attention, visual learn- ing, and working memory and then tracks changes over time through follow-up assessments. Cognigram, however, does not require a baseline digital assessment for its screen- ing, which allows doctors to iden- tify patients for further tests, says O’Connor. Instead, on its first use, the patient score is compared to an age-matched normative dataset. In subsequent tests, patient scores

Normal

Mild Cognitive Impairment, Early Alzheimer’s Disease

Alzheimer’s Disease

Linus later acquired, has the pa- tient draw the clock using a stylus on the iPad while an AI algorithm tracks the movement of the hands, measuring a wide array of vari- ables, including the time it takes to respond to instructions, the size and characteristics of the draw- ing itself, and the way the patient moves their hands. The AI algo- rithm was trained on thousands of patients with dementia of varying severity, as well as healthy people. Thedataweregatheredfromlocal

can reliably identify buildup of amyloid plaque in the brain, a hall- mark of Alzheimer’s. The paper was published in Neurology in 2021.

The assessment is simple enough to do in a primary care practice during an annual wellness visit, administered by a medical as- sistant with minimal training. The company has raised $64 million since its founding in 2019 and com- pleted early testing of the product in 2023. The product is now being rolledoutintheIndianaUniversity

SCIENTIFIC AMERICAN CUSTOM MEDIA 49

are compared to both the normative dataset and previous patient scores.

The test, which can be admin- istered by a medical assistant in a doctor’s office or even done remotely from home, performed well in several studies, including one published last year in the Journal of Alzheimer’s Disease in December. It compared the performance of 4,871 cognitive- ly unimpaired adults to that of 184 adults who met clinical criteria for mild cognitive impairment.

“It all sounds very simple,” says O’Connor, “but these tests have been proven to be really sensitive to the earlier stages associated with disease.”

Cognivue, based in Victor, New York, recently released a digital cog- nitive testing technology that first screens for potentially confounding factors like visual and motor impair- ments, then adjusts the test to ac- count for these impediments, which otherwise can muddy the results. It does so by displaying a bunch of white dots on a black screen contained in a green, wedge-shaped outline. As the dots move in clockwise and counter- clockwise directions, the patient is instructed to keep the dots within the green wedge by turning a knob that controls the position of the wedge.

To measure cognitive impair- ment, the program then asks patients to distinguish real words displayed on the screen from nonwords or to distinguish letters from random symbols. Other tests ask the test sub- ject to distinguish between different shapes. The test increases in difficul- ty until the subject reaches the limits of their abilities.

The Cognivue program uses AI algorithms to evaluate patient per- formance in visual acuity, memory, executive function and other areas, as compared to people with similar age, education levels and other de- mographic factors.

Adam Piore is a freelance journalist based in New York.

50 THE NEW AGE OF ALZHEIMER’S

Gateway to the Brain

The optic nerve is a link to the brain—and potentially to disease diagnosis.

The big goal for firms that are devising tests for Alzheimer’s is to find a simple, inexpensive one that is reliable enough to provide definitive diagnoses—something that could replace en- tirely the need for expensive PET scans and cerebrospinal fluid biopsies. Scientists at Toronto-based RetiSpec believe that reti- nal scans might eventually meet this bill.

The eye is linked to the brain by way of the optic nerve, so changes in the brain—including the buildup of amyloid plaque from Alzheimer’s—are reflected in the retina. RetiSpec has developed “It all sounds

a device that beams light on to very simple,

the retina and measures the light reflected back. It then analyzes but these tests

the output using AI algorithms have been

trained on other retinal scans proven to be

collected from thousands of Alz- heimer’s patients who had tested really sensitive

positive on PET and cerebral spi- to the earlier

nal fluid tests.

stages

The device is an attachment that can be screwed on to a device, associated

called a fundus camera, that most with disease.”

eye and neurology specialists, and

some primary care physicians, al-

ready have. Although the compa- ny has not yet set a price for the device, officials say that the cost per test will fall below $1,200. Whereas normal fundus cameras capture three wavelengths of color, red, green and blue, the at- tachment consists of a hyperspectral sensor that can capture a wider band of frequencies, most of which are not visible to the

naked eye.

Hyperspectral sensors have detected Alzheimer’s disease in

lab mice. CEO Eliav Shaked says a multicenter, blinded vali- dation study showing the company’s AI-based retinal test can predict amyloid-beta brain pathology in a diverse population of adults with preclinical, mild cognitive impairment, and prob- ably Alzheimer’s disease, is under review at a scientific journal.

RetiSpec hopes eventually to win FDA approval for use as a diagnostic tool, rather than just for purposes of screening. Retinal scans, he says, are more convenient than blood tests because they can provide a diagnosis immediately and don’t re- quire the use of sensitive diagnostic equipment currently need- ed to analyze blood samples. The company is testing the device at 20 clinics and doctor’s offices, in partnership with Evergreen Health and Advent Health. It is slated to begin feasibility test- ing with the FDA in early 2024. Shaked expects the technology will be available in early 2025. —AP

REINEG/ADOBESTOCK

Retina

The layer that converts light into electrical signals

Sclera

The white outer layer of the eye

Choroid Lens

A network of blood vessels that support the retina

Bends light to land on the retina

Iris

Modulates how much light the eye accepts through the pupil at its center

The eyes are windows not only to the soul but also to the central nervous system. With a direct connection to the brain via the optic nerve, the eye can provide a relatively noninvasive way to spot evidence of Alzheimer’s before clinical symptoms occur. The eye has been a subject of interest to Alzheimer’s researchers since 2003, when a study found traces of amyloid beta in the lenses of people with Alzheimer’s (analyzed postmortem). Other possible detection sites have been identified since, with retinal scans currently the most promising for clinical use. —KP

123

The lens—already rich in proteins—collects enough amyloid beta to be detected in samples from cadavers. In 2021, a team of U.S. researchers reported that

a laser imaging technique successfully screened a small sample of patients for Alzheimer’s. Tissue samples could also be collected during cataract surgery.

Optic nerves

The collection of nerve cells that carry electrical signals to the brain’s occipital lobe for processing

The vitreous humor is a jelly that fills 80 percent

of the eye’s volume. The original 2003 cadaver study found that it contains the same levels of amyloid beta and tau as cerebro- spinal fluid. More recently, amyloid and other biomark- ers in vitreous humor were linked with Alzheimer’s decline in living people, too. Clinical tools, however, are not in active development.

The retina, the collection of neurons where light- detecting rod and cone cells are housed, has emerged as a promising Alzheimer’s diagnostic. The tests being developed, including one by a team

in Toronto, would image the retina using different wavelengths of light to detect the protein clumps that form as Alzheimer’s begins to set in.

Vitreous chamber

The space—filled with vitreous humor— inside the eye

Ciliary muscle

Adjusts the lens shape to focus light from both near and far sources

Lets in light from the outside world—the white sclera becomes clear here—and directs it through the pupil and into the lens

SCIENTIFIC AMERICAN CUSTOM MEDIA 51

Cornea

[ INFOGRAPHIC ] Risk Factors

Brain Health

Because Alzheimer’s degrades and eventually kills neurons, a healthy brain is one of the best defenses.

Lack of schooling

Educational attainment— particularly before age 20— correlates strongly with decreased risk of dementia in adulthood.

Depression

People who show depressive symptoms in a screening are twice as likely to develop dementia.

Traumatic brain injury

Significant damage to the brain, such as from car accidents, sports injuries and falls, modestly increases dementia risk.

for Alzheimer’s

Genes and age play a big role in susceptibility to the disease, but choices make a difference, too.

Scientists are still learning about the causes of Alzheimer’s, but most agree that many factors contribute to an individual’s risk of getting the disease. Some risk factors, such as age and genes, are inescapable. Others can be modified with lifestyle changes, such as exercise and nutrition—in one study, participants were able to reduce their risk of getting Alzheimer’s by 60 percent. Although most risk studies focus on dementia in general, here are important findings about the known risk factors as they apply to Alzheimer’s. —KP

KEY

Risk factors—marked —are arranged by category and listed in order of importance.

Squares mark the proportion of cases attributable to a modifiable risk factor:

Genetics

Researchers have identified more than 70 genes associated with Alzheimer’s. Some increase risk, while at least one protects against it. Almost none guarantee their carriers will (or won’t) develop the disease.

Familial Alzheimer’s

This inherited form of the disease accounts for fewer than 1 percent of cases, most beginning before age 65.

APOE4 and other genes

Genetics is the main factor in 60 to 80 percent of Alzheimer’s cases, researchers estimate. The most widely studied gene, APOE4, seems to slow the brain’s ability to clear amyloid beta and to make tau tangles easier to start forming. Dozens of other genes are implicated as well, and the list continues to grow. The best defense is to detect the disease in the early stages.

Most (8 percent) Least (1 percent)

Cognitive reserve

A sharp, curious mind may help stave off some of the cognitive decline of Alzheimer’s disease. In the 1980s, researchers found from autopsies of older adults that the brains of some highly intelligent, mentally active people with no signs of dementia still harbored the plaques and tangles associated with Alzheimer’s. They reasoned that “cognitive reserves” allow the brain to adapt to these physical changes by finding alternative pathways for thinking and recall. Recent studies suggest that having

high levels of cognitive reserve, developed over a lifetime of stimulation and curiosity, reduces the risk of symptomatic Alzheimer’s by about 40 percent. Brain health, it seems, matters.

Environment

Recent years have identified air pollution as a major risk factor. (Aluminum, once thought to be a major culprit, has been cleared of blame.) Other factors, such as radiation, noise and climate change, may also play a role.

Air Pollution

Tiny particulates from cars, smokestacks and forest fires can pass from the nose to the brain, where they may promote amyloid deposition.

THE NEW AGE OF ALZHEIMER’S

Source: Risk factor relative importance: G. Livingston et al., The Lancet, 396, 413 (2020).

Age

Past age 65, the rate of Alzheimer’s doubles every 5 years; one-third of people over 85 have the disease. Age is

the single most important risk factor identified for late-onset Alzheimer’s (about 85 percent of cases). Age is beyond our control, but watching for early symptoms and intervening as soon as possible to slow the disease’s progression improves outcomes. For a list of early signs of dementia, see “How to Detect Alzheimer’s Before Symptoms Appear,” on page 47.

Normal brain aging

Mild cognitive decline occurs naturally with age, but people with Alzheimer’s typically see a much faster drop-off.

Cognitive function

Age

Source: “Alzheimer’s Disease and Other Dementias,” Mayo Clinic, 2020.

Lifestyle

An active, healthy lifestyle protects against Alzheimer’s and other dementias, though it’s dif- ficult for scientists to determine precisely how. These factors have well-established links.

Social isolation

Social contact—through friend- ships, family, marriage and work—seems to provide long- term cognitive benefits, including reduced risk of all dementias.

Alcohol Use

One large study in the U.K. found that for heavy drinkers, every seven additional drinks per week increased dementia risk by 17 percent.

Body Health

Poor physical health can raise the risk of Alzheimer’s. Here are six ways for which evidence is strong.

Hearing loss

People who lose their hearing in middle age are about twice as likely to develop dementia. Regular testing and use of hearing aids (if needed) can lower risk, though evidence is weaker for Alzheimer’s.

Smoking

People who have never smoked developed Alzheimer’s two- thirds as often as smokers and ex-smokers. Quitting makes people less likely to develop other dementias.

Hypertension

High blood pressure increases the risk of all dementias, but treating the condition with drugs lowers the likelihood of cognitive decline. Anti-hypertension medication seems to slow the progress of Alzheimer’s.

Physical inactivity

People who exercise regularly in middle age reduce their Alzheimer’s risk by 45 percent, one meta-analysis found.

Diabetes

People who have had type 2 diabetes develop dementia at higher rates—1.6 times as often for men, 1.8 for women. It’s not yet clear whether medications reduce that risk.

Obesity

A body-mass index of 30 or higher is correlated to a higher risk of dementia.

Normal Abnormal

Optimal aging

r’

SCIENTIFIC AMERICAN CUSTOM MEDIA 53

The case for sleep

Studies in mice have shown that cerebrospinal fluid in the brain and spinal cord acts during sleep to clear amyloid beta. Another study followed 8,000 Britons

for 25 years and found those who got six or fewer hours sleep in their midlife years were 30 percent more likely to develop dementia.

Weak links

Studies have provided hints that the following factors may also lower dementia risk (though so far solid evidence is lacking):

• Maintaining good eyesight

• Living in a quiet neighborhood

• Preventing gum disease

• Following a Mediterranean diet

• Speaking two languages

• Keeping blood iron levels healthy • Staying current with vaccinations • Sitting less than 10 hours a day

• Spending time in nature

• Avoiding certain laxatives and acid reflux medications

A Grassroots Approach to Diversity

Community-based programs are working to reverse decades of underrepresentation by building trust among clinicians, researchers and everyday people.

BY SIMAR BAJAJ

54 THE NEW AGE OF ALZHEIMER’S

When Chris Tann was diag- nosed with frontotemporal dementia, he and his wife Debra drove seven hours, each way, to Vanderbilt University in Tennessee to participate in a clinical trial, returning several times each year for follow-up visits. Clinical research in or around their commu- nity in Valdosta, Georgia, was virtually nonexistent.

Debra Tann, who is a certified dementia educator, has a front-row seat to the disproportionate impact Alzheimer’s disease and related dementias have in communities of color. She has lived in Valdosta, a city of 56,000, whose population is primarily Black,

“Brain health equity begins in the lab.”

for three decades and has made it her mission to educate and em- power members of her community to participate in clin- ical research. Be-

yond simply promoting equity, what’s at stake is the development of tailored treatments that could help stop dementia in communities of color nationwide.

Clinical trials have long been hindered by a lack of diversity, where people of northern European de- scent are significantly overrepresented and Black, Latino, Asian and Indigenous peoples are left out. This problem is especially acute for Alzheimer’s dis- ease. For example, the phase 3 trial of the promising new drug donanemab enrolled 1736 people, but only

SCIENTIFIC AMERICAN CUSTOM MEDIA 55

35 Black and 59 Hispanic participants, represent-

the differences in disease biomarkers between peo- ing 5 percent of the study. Likewise, lecanemab, the

ple of differing ancestries,” says Nancy Lynn, a senior first Alzheimer’s drug to receive full approval by the

vice president at the BrightFocus Foundation and co- U.S. Food and Drug Administration, was tested in a

leader of the project engaging local communities in 1,795-person trial, but only 2.5 percent of the partici-

Alzheimer’s research in Valdosta. “Brain health eq- pants were Black and 12.5 percent Hispanic.

uity begins in the lab.”

Across more than 100 Alzheimer’s drug trials, 95 percent of participants were white, a percentage that’s remained stub-

bornly high over the past

20 years. The lack of rep-

resentation may be even

greater than these num-

“We got bers would suggest be-

cause Black patients are

Tylenol and twice as likely as white

Ibuprofen patients to have demen-

How did we tia, while Hispanic pa-

tients are 1.5 times as

get them? likely. “The vast amount

They had to of our research and un-

be researched. derstanding of Alzhei-

mer’s—and other related

You may not dementias—are based on

know that these rarefied, highly

because us educated, high socioeco-

nomic status, non-Latinx

Hispanics white samples,” says

weren’t asked Monica Rivera-Mindt, a

to participate professor of psychology

at Fordham University.

in this research.” Despite their higher

rates of dementia, people

of color more often fail

to qualify for trials than

white people. In gener-

al, marginalized groups are ruled out because they have a higher rate of comorbidities and their blood screenings reveal lower levels of Alzheimer’s pathol- ogy than white people with similar disease progres- sion. In addition to steering Alzheimer’s research and development away from people of color, these disparities draw into question our understanding of the disease itself. “It’s a terrible waste of time, efforts

and resources to start going down the wrong path for the next 30 years because we don’t understand

Reversing decades of underrepresentation is not a short-term project, and it involves years of build- ing trust among clinicians, researchers and everyday people. Through community-based programs, scien- tists and activists are beginning to do the work of bridging the gap between the medical establishment and local communities. The program in Valdosta and another in Rio Grande City, Texas, demonstrate the need to move beyond a one-size-fits-all approach and toward a more personalized model for Alzheimer’s clinical trials.

Community-led trials

Even though Starr County, Texas, has the country’s highest dementia rate—more than a fifth of Medi- care beneficiaries are affected—Alzheimer’s clinical trials had never been conducted in the county. In 2021, however, the El Faro Health and Therapeutics opened its doors with the mission of enlisting the community of Rio Grande City, an overwhelmingly Hispanic enclave, in clinical trials.

The clinic was started by Antonio Falcon, a trust- ed healthcare professional and a pillar of his com- munity. When his son, James Falcon, returned home after serving as an emergency room physician in the U.S. Army, they decided to tackle the challenge of bringing local residents into the mainstream of Alz- heimer’s research.

With support from the Global Alzheimer’s Plat- form, El Faro has focused on providing more op- portunities for Latinos to participate in Alzheimer’s research. Jessica Cantú, a nurse practitioner and the site director, hosts community events twice each month, where she explains to members of the com- munity how “research” differs from “experimenta- tion,” how safeguards like consent forms protect par- ticipants, and why it’s important to be represented in clinical trials. “I always tell them: We got Tylenol and Ibuprofen. How did we get them? They had to be researched,” she says. “You may not know that

TILIL/ADOBESTOCK

56 THE NEW AGE OF ALZHEIMER’S

“All we do is educate, educate, educate. We’re from here, so most people either know our parents or grandparents, so they’re able to say, ‘Okay, they are so-and-so’s daughter. I trust them a little more.’”

because us Hispanics weren’t asked to participate in this research.”

Cantú has also helped launch several clinical tri- als, including one that tests whether donanemab can prevent Alzheimer’s. Funded by Eli Lilly, this trial is enrolling 65- to 80-year-olds who have evidence of amyloid plaque in their blood, an Alzheimer’s biomarker, but no dementia, to determine whether donanemab can slow Alzheimer’s progression when compared to placebo.

For people who don’t meet the inclusion criteria for these trials, El Faro has launched an observation- al study open to anyone 18 and older, where people take memory tests on their phone or computer every three months. Part of a larger global study funded by the Davos Alzheimer’s Collaborative, the El Faro study is a digital phenotyping study, which uses data from personal digital devices to study human behav- ior with the goal of better understanding the causes of dementia.

Educate, give, then enroll

In Tann’s community in Valdosta, a third of house- holds make less than $20,000 a year. A lack of pub- lic transportation and healthcare providers who are people of color are additional barriers to accessing quality healthcare, as well as significant levels of mistrust in the healthcare system, stemming from a long history of discrimination and structural rac- ism. Tann, who founded a dementia advocacy group called Reminiscent, says that many of her neighbors associate “research” not with hope and opportunity,

but with past atrocities such as the Tuskegee study of untreated syphilis and a legacy of transactional ar- rangements. An effort to immediately try and enroll residents would likely have failed.

As a result, Tann is focusing first on educating people about dementia, partnering with them, and winning their trust. For two years, with support from BrightFocus Foundation, she has held more than 100 community events in Valdosta, ranging from dementia-specific activities like educational workshops and quarterly brain health screenings to more general community-building exercises. These include offering complimentary fitness classes for community members, producing free informational webinars specific to Valdosta, hosting community dinners and a holiday party for elders, organizing a Respite Cruise for caregivers, and providing demen- tia training for professionals and families.

The ultimate goal is to bring a brain health center to Valdosta that will conduct clinical trials, train pro- viders in dementia, and engage everyday people in prevention. By part- nering with the com- munity to provide these health-promoting activi- ties, the Valdosta pro- gram aims to establish trust and educate people about brain health, likely offering spillover ben- efits for other conditions like diabetes and cardio-

vascular disease.

“We are taking ‘the

backdoor approach’,” Tann says. “We are not in the face of our community; we’re tiptoeing in to find out where they are.”

Building trust and understanding requires mov- ing at the pace of the community, rather than fol- lowing a specific mandate. For now, Tann plans to begin recruiting community members in mid-2024 for a research study that people can participate in from their homes.

Simar Bajaj is a freelance writer.

“We are not in the face of our community; we’re tiptoeing in to find out where they are.”

SCIENTIFIC AMERICAN CUSTOM MEDIA 57

“We need genomics at a global scale”

Elias Zerhouni says expanding research to include a diverse cohort is essential to beating a disease that is far more complex than researchers understood two decades ago.

BY FRED GUTERL

ILLUSTRATIONS BY OBOH MOSES

When Elias Zer- houni took over as director of the National Insti- tutes of Health

in 2002, the only way doctors could know for certain whether a dementia patient had Alzheimer’s disease was to perform an autopsy.

A few years later, new technol- ogies that could deliver a definitive diagnosis revealed an embarrass- ing truth: many of the ongoing clinical trials for Alzheimer’s treat- ments included a significant num- ber of subjects who had been mis- diagnosed. “We didn’t know who had the disease and who didn’t have it,” Zerhouni recalls.

It fell to Zerhouni and his col- leagues at NIH to fashion a research program that could exploit the power of the new diagnostic tech- nologies—which now include im- aging, biomarker tests and digital cognitive tests, among others—to learn about what has turned about to be a hugely complex disease.

Since leaving NIH in 2008, Zerhouni has carried on that work in various roles—as head of re- search at Sanofi from 2011 to 2018 and, currently, as a founding board member of the Davos Alzheimer’s Collaborative (DAC). He is helping DAC assemble a cohort of Alzhei- mer’s patients that reflect t he world’s genetic, environmental, so- cial and economic diversity, which he believes is crucial to under- standing and treating the disease.

58 THE NEW AGE OF ALZHEIMER’S

DAC’s Global Cohorts program has so far engaged 26 different coun- tries, with the goal of drawing up to one million people from rich and poor nations alike in North America, South America, Africa, Europe, Asia and the Middle East.

Expanding research to include a diverse cohort is essential to treating Alzheimer’s disease, he believes. Still, new drugs that can slow the progress of Alzheimer’s, despite their limitations, are a turning point, and bode well for the future. “Progress in medi- cine tends to occur like a swarm around a fortress,” he says. “When there is a crack in one place, you have a lot of people going through that crack, not knowing if it’s a dead end or if it’s the beginning of redemption.”

Scientific American Custom Media talked with Zerhouni about the last two decades of Alzheimer’s research and his vision for what needs to happen going forward.

SCIENTIFIC AMERICAN CUSTOM MEDIA:

You’ve had a bird’s-eye view of many different human diseases. How is Alzheimer’s unique?

ZERHOUNI: A perfect life is: you are born, you’re healthy, you re- main healthy, and you die.

However, that’s not what you see. What you see is that you have a healthy beginning after childhood illnesses, you’re pretty healthy un- til about 50, when there are some cancers. For many people who live longer and remain physically healthy, cognitive impairment be- cause of neuronal degeneration leads to a more profound loss of quality of life.

Alzheimer’s is a slow pandemic. It’s growing along with the preva- lence of obesity and diabetes and with aging populations almost worldwide. It has a huge econom-

ic impact—a permanent impact, because you have a population of patients that could have been healthy and self-sufficient but no longer are.

We found that if you delayed the onset of Alzheimer’s disease by five years, it would reduce its burden on society by 50 percent. We also found that the mortality of caregivers—the wife who takes care of the husband and vice ver- sa—is extremely high.

If you do not have a function- ing neural system, you can’t have a functioning body. That’s not

could stop a virus. After that, a lot of researchers said, “Wait a min- ute, maybe we can develop a better AZT. Maybe I can get one against this part of the virus or that part of the virus.” Today, you have triple therapies that control the disease for years.

After years of disappointment, the news about Alzheimer’s research has only recently gotten brighter. How did we get here?

When I became NIH director in 2002, we could see the evolution

“Progress in medicine tends to occur like a swarm around a fortress. When there is a crack in one place, you have a lot of people going through that crack, not knowing if it’s a dead end or if it’s the beginning of redemption.”

just Alzheimer’s, it’s neuroscience generally. The number-one cause of disability between the ages of 25 and 44 is depression. The im- pact of a cognitive deficit is often much greater than the impact of a physical deficit.

Why is the medical field so excited about the recent treatments for Alzheimer’s?

It’s the first crack in the mystery of the disease. In medicine, progress is never a delta function, where you havenotreatmentandthenallofa sudden you have a treatment.

HIV is a good example. We were desperate in the mid-1980s. People were dying right and left. And then we had a cancer drug called AZT that had some effects. It showed that it was doable. It changed the paradigm.

At the time, no one thought that a drug, a small molecule,

of the disease when it became clinically relevant and clinically obvious. We had no idea what hap- pened before you were symptom- atic. When I reviewed the [NIH research] plans for Alzheimer’s, I said that we would be unlikely to reverse a disease process that has destroyed so much of the brain’s tissues, [including the] neurons important for memory and behav- ior. It’s almost like waiting for the plane to crash and then trying to put it back together.

By 2018, after spending $20 billion on clinical trials, all the phase 3 trials of the major com- panies failed. People were desper- ate, wondering what went wrong and what happened. By then I had become head of R&D for Sanofi, a major pharmaceutical company, which had a program for Alzhei- mer’s disease. I found the same issues. We had no ability to truly diagnose the disease properly. We

SCIENTIFIC AMERICAN CUSTOM MEDIA 59

had no biomarkers. We couldn’t do a biopsy of the brain to confirm a diagnosis, like you can do in cancer. We didn’t know who had the disease and who didn’t have it.

On top of that, almost all the research was being done on Cau- casians and on patients in rich countries. The knowledge base was fragmented, incomplete and incoherent.

Is that when you realized that Alzheimer’s researchers needed to study a larger and more diverse population?

At NIH, we funded quite a few in- vestigators looking at Alzheimer’s disease. As we did this, we realized that every investigator had a few hundred patients here, a couple thousand there, 500 over here, and so forth, all around the world. But nobody had the critical mass of patients you need to understand variations between individuals and what drove those variations.

As biomarker tests improved, we realized that in many of the trials, perhaps 30 percent to 40 percent of patients did not have Alzheimer’s disease. They had dementia from other causes. We had an incom- plete hypothesis in a group of pa- tients who don’t even represent the disease we’re studying.

Was there any value in that work?

When we looked at the data on thousands of patients from the various phase 3 trials, all of the patients who had had a response to treatments were early-stage Al- zheimer’s patients who had only just started to develop symptoms. Patients who had established memory impairments did not im- prove. That told me that my anal- ogy—that you can’t put a crashed plane together again—was true. It also told me that you could prevent

a plane crash if you knew that the engines were having trouble early enough to make a correction.

About this time, George Vradenburg asked me to speak to a meeting in Lausanne with a specific question in mind: “Don’t talk to us about what didn’t work. Don’t talk to us about what failed. Just tell us what ideas you think we should really consider to ad- vance the field.”

In the talk, I said that to un- derstand a disease, you cannot just study people with the same genetic background as one anoth- er. When you look at the genetics of patients with Alzheimer’s, there

“If you have a diversity of patients from around the world, you can extract the disease- related mutations or changes by comparing populations.”

was a group of families in Colom- bia that had a very high frequency of the disease, which led to the dis- covery of a mutation in the gene that produces the presenilin pro- tein. It was later confirmed in oth- er groups, which shows the power of comparative genomics. More re- cently, a 73-year-old patient from the affected families in Colombia did not develop Alzheimer’s dis- ease, leading us to begin search- ing for the protective mutation that made her resistant, despite her predisposition for Alzheimer’s.

You couldn’t interpret it be- cause all comparisons had been done within the same group.

Also, I didn’t think we knew what the natural evolution of the disease was in any one patient. Some patients develop symptoms and decline very quickly, and oth- ers decline much more slowly.

60 THE NEW AGE OF ALZHEIMER’S

“If you delayed the onset of Alzheimer’s disease by five years, it would reduce its burden on society

by 50 percent.”

Why? That’s the central question in Alzheimer’s research. Are there unknown protective mutations that could be exploited for novel therapeutics? I had the sense that we didn’t quite understand what was going on and that we needed to find out by studying a more di- verse global population.

The number-one rule in drug development is: understand the biology. The number-two rule is to understand the epidemiology of the disease—when do you inter- vene? The third rule is, do you have the right population in your trial?

What needs to happen going forward to get Alzheimer’s to the point where it’s a manageable disease?

We need genomics at a global scale. That allows you to compare and separate environmental effects versus disease effects and dis- cover protective mutations. That is why we want to expand DAC’s Global Cohort program to include 100,000 people.

If you have a diversity of pa- tients from around the world, you can extract the disease-related mutations or changes by compar- ing populations. You can also ex- clude environmental factors. For instance, people in Africa have a much lower incidence of colon can- cer than people in America. Re- search has found that the heavily meat-driven diet of the developed

world is driving the incidence of cancer. By comparing environ- mental effects around the world, you can come up with conclusions and discover what is driving the disease in the first place, as we did for hypertension and cholesterol.

Solving Alzheimer’s is like scaling a 100-foot cliff, and we have ten 10-foot ladders. Wouldn’t it be better to put them together and have a 100-foot ladder so we can get over the cliff?

If you found a patient with this disease who had the same genetic background as someone else, and one of them was a fast progressor and one of them was a slow pro- gressor, you’d ask: “What is pro- tecting the slow progressor from declining faster?” This is what we look for in genomics. By looking at the genome of all these patients and comparing them, we find mu- tations that are protective. That’s important for discovery and for treating this disease.

How many people do you have now in the Global Cohorts program?

22,000—it’s the largest cohort in the world right now.

What is the challenge of getting to 100,000?

It’smultifactorial.Firstofall,Alz- heimer’s is a long, chronic disease. We want to focus on existing co- horts that have followed patients for a long time already. You don’t just go in and say, “Who wants to do this research?” and then wait for 20 years before you have the co- hort. We’re trying to build on what is already existing that has enough of a longitudinal timeline that will essentially make the 100,000 we select very powerful immediately.

Second, quality has to be stan- dardized. We have to have a central lab for blood tests. That requires

a lot of collaboration, coopera- tionandnegotiation.Forexample, China does not allow the export of DNA from Chinese citizens. So, we have to have a lab in China, but then we have to have an agreement that the data will be shared.

Every center we’ve approached has been willing to share data in a federated way. Gates Ventures is funding our digital backbone and data analysis and is willing to pro- vide the framework. Ethics is also important. You absolutely have the obligation to get informed consent, especially if you do new types of studies. That takes time.

There is also a clinical trial network, in parallel to the cohort, which is pre-positioning interest- ed scientists worldwide to be able to conduct proof of concept trials quickly. A study of 1,000 patients is ongoing to test the various bio- markers that are being proposed, so that we can select the best ones, including novel digital biomarkers using smartphones, for the cohort. It’s a heavy lift that requires a lot of time and resources.

Aside from assembling a large co- hort, what else needs to be done?

When do you know if someone has the disease and will develop a more severe form? Discovering biomark- ersiscritical.Ifyouthinkthatyour therapy is only effective early in the disease, then you need to have a reliable way of detecting who that is who deserves the treatment. To do that, diversity is important be- cause blood is not the same blood everywhere in the world.

What about digital biomarkers?

Typically, when you want to diag- nose mild cognitive impairment, you use a series of tests. The doc- tor gives you seven words to mem- orize, makes you do something

SCIENTIFIC AMERICAN CUSTOM MEDIA 61

else, and then 15 minutes later, asks you again. Other cognitive tests focus on ideation, rational ability, and so on. They are all de- pendent on cultural context—on where the test is given and what doctor or nurse administers the test. It’s an extremely noisy signal. This makes it difficult to catego- rize patients in a meaningful way.

A digital biomarker is, you take your cell phone and I ask you to type in a few words. I can mea- sure the speed at which you type and I can measure it over time. It’s an objective measure. We know from research that a person’s voice print changes with the onset of Alzheimer’s disease. So does the ability to verbalize. We can mea- sure them and, with artificial in- telligence, we can classify it.

A researcher in England used the U.K. Biobank, which has ac- cumulated 500,000 patients over the past 25 years. Then they asked the question, who among those patients developed Alzheimer’s disease? We know that a muta- tion called APOE4 is a good pre- dictor of whether or not you will develop Alzheimer’s disease. This researcher recorded the voices for a whole series of patients and, lo andbehold,thevoiceprintanaly- sis could actually detect the pa- tients that had APOE4 mutations.

There are many factors that contribute to Alzheimer’s disease that need to be discovered. The cohort program of DAC is creating a critical mass of diverse patients that represents the global nature of the disease and that can be used to separate environmental effects from biological ones and discover clues to protective mutations.

As you look at large popula- tions, you immediately realize that what we call Alzheimer’s disease is not one disease, it’s multiple diseas- es that each have very different out- comes. To have a one-size-fits-all

approach to this complex disease does not serve us well. Many in the field are coming to the conclusion that there may be at least two kinds of Alzheimer’s: inflammatory and noninflammatory types.

We’ve talked a lot about genetics as a risk factor. What would you like to know about environmental or geographic factors?

What I would like to know is whether there is differential inci- dence in different countries. Is the U.S. getting a higher incidence of Alzheimer’s than people in Ugan- da? And if so, why?

Is there any feeling that environmental factors play a big role in Alzheimer’s?

[Laughs.] It’s hard to think it will be environmental. Alzheimer’s was discovered a century ago. Unlike heartdisease,whichwaslowinthe early part of the century and then became high and deadly in the ‘50s, ‘60s and ‘70s, we haven’t seen that in Alzheimer’s. We are seeing more Alzheimer’s because life ex- pectancy has gone up. But I’m not seeing a complete change—a com- pletedelta.Whenyouseeadeltain epidemiology, that’s when you sus- pect an environmental cause.

But there has been a rise in obesity and heart disease, which are linked to Alzheimer’s.

Yes, there are certainly aggravat- ing factors, no question about it. Lack of exercise, lack of mental stimulation, obesity, sedentari- ness, loneliness, mental health— all of those are aggravating fac- tors. I don’t think that they’re causal, but that is my opinion. The one thing you have to learn in this business is humility because the mystery is bigger than all of us.

What would you tell someone who was diagnosed with early- stage Alzheimer’s right now?

The cofactors need to be acted upon—if you have heart disease, diabetes, obesity, you absolutely need to put yourself in a good health status. We also know that some medications can delay [the onset of symptoms], but they are only effective for a year or two.

It all depends on the age of onset. If the age of onset is 75 or 80—like President Reagan, for example—you can manage it for three to four years. If it happens earlier, that is where the need for new therapy is. You could propose [taking] antibodies that have just been approved, but we know that it’s about 18 months to stabilize, and we don’t know what the long- term slowdown of the disease would be.

IstheU.S.healthcaresystem adequate to tackle Alzheimer’s?

It’s an absolutely critical question. The U.S. healthcare system is not geared towards prevention. There is also a lack of preparation of the healthcare system to deal with a slowly growing chronic disease. And that is a focus of the health- care preparedness component of DAC. Look at obesity—we’re not dealing with it. Do you think we’re dealing with diabetes? We’re not dealing with it. The U.S. health system is designed for acute, in- terventional care, not the long- term, low but steady care that is required to prevent disease.

Prevention is not paid for in our system. Why? Because in large part insurance companies change clients every year or two. If you are an insurance company and you say, “I’ll pay for your prevention,” next year you’ll be someone else’s client. I don’t know that I have a

62 THE NEW AGE OF ALZHEIMER’S

5 +

SOCIETAL BURDEN

“The U.S. health system is designed for acute, interventional care,

not the long-term,

low but steady care that is required to prevent disease.”

I don’t think you’ll have critical mass for early Alzheimer’s disease. It would have some value be- cause then you can compare the genomes of people with Alzhei- mer’s with people who have no Alzheimer’s. But it’s not compre- hensive enough and integrated enough around this disease process. And remember, the economic impact of Alzheimer’s is huge, in addition to the huge cost to health.

The U.S. alone wouldn’t really be able to have a Manhattan Project, because of the lack of diversity. You really do need the breadth of a global effort.

That is my position, yes.

Unlike cardiovascular disease

or cancer or many other diseases, there’s something taboo about the brain. You cannot biopsy the brain. You cannot really inva- sively study the normal brain or the Alzheimer’s brain. We biopsy cancers all the time, we put cath- eters all around the vessels, we’ve developed angioplasty and stents and so on and so forth. But the culture of neuroscience is much more conservative. Even though we know that the micro-biopsy of the brain is doable without being life-threatening or mind-altering, we have an aversion to it. For ex- ample, simple spinal taps are well accepted in Europe but not in the U.S., which greatly hampers re- search in Alzheimer’s disease.

If you look at the history of medicine, the heart used to be taboo as well. In the ‘30s, doctors felt that if you tickle the heart with the catheter, it would stop. It was dogma that you couldn’t touch the human heart, until a cardiologist in Austria, Werner Forssmann, did it and got the No- bel Prize for it. We are at the same stage in neuroscience as we were in the 1930s with cardiology. ■

DELAYED AD YEARS

DOWN 50%

solution, but clearly Alzheimer’s

to provide a phased, milestone- is going to present a conundrum

based approach to the program. because it’s a disease that requires

early intervention to prevent dam-

What would a Manhattan Project in the U.S. for Alzheimer’s

age later on, a little bit like diabe-

look like? Does any other

tes and heart disease.

country have one?

Is there anything that the U.S.

government should be doing?

The U.K. comes closest because of the 500,000 patients they’re follow- Yes. There is not currently a mech-

ing in [the U.K.] Biobank. The prob- anism to have a “Manhattan Proj-

lem is lack of diversity. We have a ect” approach to a disease like this,

program called All of Us, in which but we should consider it. We’ve

a million Americans will be com- done it with HIV. But Alzheimer’s

pletely sequenced and analyzed. doesn’t seem to get the energy at

The problem with that is that you this point. The National Institute

may not have enough patients in of Aging has received more fund-

any one group to reach solid con- ing, and that’s good. DAC has ap-

clusions—a million people with plied for a grant to the NIH to be

1,000 diseases, few of which have able to support the cohort, and I

a critical mass. You’ll have enough think there is receptivity. We want

critical mass to study obesity, but

SCIENTIFIC AMERICAN CUSTOM MEDIA 63

The Urgent Challenge of Scale

To bring new tests and treatments to the people who need them, healthcare systems must transform how they approach dementia care.

DBY HILARY EVANS AND JOHN BELL

ementia robs us of everything that matters. Our memories. Our con- nections. Our story. Every three sec- onds, another person in the world hears the devastating news that they have dementia. No wonder, then, that it is the most feared condition among people aged over 55.

But, after decades of relentless research across the globe, that is all set to change.

Investments in dementia research are finally lead- ing to breakthroughs, as life-changing treatments that may slow the progression of Alzheimer’s come within close reach. And we’re understanding more

and more about how we can reduce our risk of devel- oping dementia. This progress is mirrored by active and growing investment in drug development in the

field of neurology around the world, which is fueling further innovation and drug discovery.

For a field that has seen no progress since the 1990s, when symptomatic drugs in the form of cho- linesterase inhibitors were introduced, it certainly does feel that the time to turn the tide on this devas- tating condition has finally arrived.

The power of recent scientific discoveries, coupled with lessons from a litany of past research failures, means there is now a new sense of urgency on both sides of the Atlantic. We now need to see action on two fronts: to reduce the number of people affected by dementia in the future, and to minimize its im- pact on those who do develop the condition.

But this action demands a seismic shift in the way our health systems approach dementia care. This will take time and resources, so health systems and physicians need to be supported to manage this change.

JOEY GUIDONE C/O THEISPOT

64 THE NEW AGE OF ALZHEIMER’S

The current state of play

In the past year, we’ve seen the arrival of the Alzhei- mer’s drug lecanemab (Leqembi) into U.S. healthcare and more recently, in Japan and China. A second Alz- heimer’s drug, donanemab, is rapidly following suit, and, regulatory decisions from several countries are expected over the coming months.

Although the benefits of these drugs are modest, and with significant side effects for some, it none- theless marks the arrival of a new wave of treat- ments that can slow the course of Alzheimer’s dis-

from new discoveries. Alzheimer’s Research U.K.’s Dementia Community Champions initiative aims to do exactly this, by uniting South Asian community members and empowering them to share informa- tion locally, reduce stigma, and enhance research representation.

This lack of awareness has also dampened the appetite for innovation. New technologies that could help diagnose dementia have struggled to be adopted into clinical practice. Within the U.K., the National Institute for Health and Care Excellence (NICE) clin-

ease rather than just treating its new dawn for dementia, signaling a step-change in the way it will be perceived and diagnosed.

Despite this success, we don’t have a straightforward path ahead to rapid, equitable access to these drugs once they are licensed. Work supported by the Davos Alz- heimer’s Collaborative is high- lighting shared challenges while acknowledging country-specific obstacles linked to healthcare in- frastructure, demographics, and clinical practices. For many coun- tries, the current state of play is going to make accessing these treatments practically impossible in the short term.

symptoms. It’s a

ical guidelines for

dementia are well established, yet the cognitive tests recommended for primary care professionals are quite basic. This discourages the implementation of more innova- tive cognitive tests that might be more sensitive, offer more insight or be more culturally appropriate.

This means that many people don’t get a diagnosis or are sim- ply told they have “dementia,” a general term used to describe a set of symptoms, rather than the underlying disease causing the symptoms, such as Alzheimer’s or vascular dementia. In England, one in three people living with de- mentia never receive a diagnosis, and it can take up to four years for someone under 65 to receive a di- agnosis of young-onset dementia.

Solving these issues will be

impossible without a change in

public attitudes and expectations.

Until very recently, a diagnosis of Alzheimer’s offered no hope. While receiving a diagnosis is important for the individual and their loved ones to understand what is happening in the brain, make future plans and have the opportunity to participate in research, a lack of effective treatments has left many wonder- ing “what’s the point?”

There also remains considerable fear and stigma around dementia. Many people and communities don’t understand that dementia reflects physical diseases of the brain, which can be overcome by re- search. Recent insight work by Alzheimer’s Research U.K. suggests that many people struggle to name de- mentia’s effects, with less than 5 percent of people aware that it can cause a loss of body and motor con- trol, stop people from being able to communicate, and create difficulty managing finances. We cannot accept that so many people see dementia as an in- evitable part of aging any longer, and improving un- derstanding is vital to ensuring people can benefit

Further compounding this problem is a profound lack of motivation to invest in cutting-edge diagnostic technology from industry, governments, and healthcare systems. Why commit resources to new, expensive tools when, sadly, a his- torical lack of effective treatments means that a per- son’s Alzheimer’s will progress regardless. This has left healthcare systems worldwide grappling with a glaring void in their ability to offer an early and ac-

curate diagnosis.

Currently, the U.K.’s National Health Service

(NHS) recommends using lumbar punctures and PET scans to detect and diagnose Alzheimer’s. These tools are effective for detecting amyloid—the hallmark pro- tein of Alzheimer’s. But it’s estimated that only 2 per- cent of people can currently access such tests because of their limited availability. England has the lowest number of PET and MRI scanners and the second- lowest number of dementia specialists, including neu- rologists, old-age psychiatrists and geriatricians, per capita among the G7 countries.

“Our healthcare systems need to be equipped with tests that can not only detect individuals who are in the early stages of Alzheimer’s but also those who are at a higher risk

of developing the disease.”

SCIENTIFIC AMERICAN CUSTOM MEDIA 65

That said, these issues are global. The Alzheimer Society of Ontario says that the introduction of a drug like lecanemab could cause diagnostic wait times in the area to skyrocket to seven and a half years, with a lack of specialist staff, biomarker testing, lumbar punctures, and PET scanners making this inevitable. In France, less than 10 percent patients with sus- pected early-stage Alzheimer’s are offered a lumbar puncture, making it difficult to identify the eligible population for these new drugs.

Potential drug-specific challenges also exist. In the donanemab trials, a radioactive agent, flortaucip- ir, identified tau, another Alzheimer’s hallmark pro- tein, in PET scans. Regulators might require a tau- PET scan as part of donanemab’s approval. However, while the FDA approved flortaucipir, now being sold byEliLillyasTauvid,itlacksreimbursementinthe U.S. and isn’t accessible in many countries. It’s un- certain whether a test that detects

tau in cerebrospinal fluid (CSF)

or alternative methods could sub-

stitute for tau-PET if donanemab

gains approval.

scalable and speedy tests that can not only diagnose individuals who are in the early stages of Alzheimer’s, but can pinpoint those who are at a higher risk of developing the disease.

Emerging tools and technologies, like digital cognitive tests that are more sensitive, mean phy- sicians can now detect early signs of diseases like Alzheimer’s, surpassing traditional pen-and-paper tests. However, healthcare systems like the NHS lag

No country possesses adequate

diagnostic infrastructure for the

potential surge in demand from

emerging treatments. We are

likely going to see more people coming forward for a diagnosis, at a younger age and with less obvious symptoms, as well as those concerned about their risk of developing dementia in the future. From pri- mary care physicians to specialist dementia services, healthcare systems worldwide must evolve, fostering interdisciplinary collaboration, embracing technol- ogy, and cultivating innovation to create new clinical pathways and equip physicians with the skills and infrastructure needed for this changing landscape.

Early diagnosis is key

Drugs like lecanemab and donanemab target and remove the amyloid protein that builds up in the brain as Alzheimer’s disease develops and progress- es. These drugs work best for people who are in the earliest stages of disease, when they are experiencing mild cognitive impairment, before symptoms have affected their ability to live independently

For these treatments to reach their full potential, our health systems need to be equipped with sensitive,

in implementing these technologies. With the poten- tial approval of lecanemab in the U.K. soon, the NHS must rapidly increase CSF testing access, from 2,000 to 20,000 annually to meet the specific needs of the U.K. population.

It’s crucial to acknowledge that cognitive tests and molecular diagnostics like blood tests must be- come more inclusive. For instance, cognitive tests conducted in a patient’s second language may yield less accurate results, and amyloid levels can vary among different ethnicities or because of common co-morbidities within specific ethnic groups.

While assessing cognitive changes is essential, it’s just one part of diagnosing Alzheimer’s. Measur- ing brain amyloid levels, on the other hand, cannot be accomplished through cognitive tests alone; it necessitates a PET scan or CSF sample via lumbar puncture. The current lack of global diagnostic ca- pacity means health systems are simply not fit for purpose nor for the future of dementia care, and this needs to change.

66 THE NEW AGE OF ALZHEIMER’S

“The current lack of global diagnostic capacity means health systems are simply not fit for purpose nor for the future of dementia care, and this needs to change.”

Developing a new clinical pathway

Two decades ago, the field of multiple sclerosis was presented with an opportunity that is similar to what we have today in dementia. MS was once a con- dition without any effective treatments, but thanks to research, it is now something people can live with while enjoying a good quality of life. This required the development of new pathways, rapid assessment units, and upscaling of multidisciplinary teams and nurse specialists. These changes improved outcomes for all patients, not just those eligible for the specific treatment, and provided the infrastructure to allow for the rapid adoption of new treatments as they be- came available.

Dementia is now going through the same gear- shift, and thankfully in the next decade we will be seeing a very different picture to today. But action needs to begin now, and this will require concert- ed efforts from across a broad base of practitioners from primary and community care, as well as sus- tained investment.

With the arrival of lecanemab already under- way in the U.S. and Japan, health systems urgently need to increase access to CSF sampling from lum- bar punctures and invest in greater provision of PET scans to determine the eligible patient population for this first wave of new treatments.

Health systems must also be supported to embrace innovation in the form of digital cognitive tests, to be rolled out as triaging assessments in primary care, before those who are identified as at risk are offered more in-depth clinical assessments such as CSF sam- pling via lumbar puncture or PET scanning.

Against this backdrop, diagnostic blood tests for measuring amyloid and tau levels are advancing rapidly. Some are already in pilot programs in the U.S., Europe, and parts of Scotland. Within the next five years, these tests are expected to become both scalable and more cost-effective than PET scans or lumbar punctures and could be offered to people in local healthcare settings or even as a finger-prick test at home.

Considerable capacity-building is needed for these tests to transition from labs to healthcare settings, including addressing challenges like freezer storage, cold supply chains, staffing, and regulatory approvals. But this requires resources and infrastructure that don’t necessarily exist right now.

New tools and techniques also require new train- ing. A survey conducted by Alzheimer’s Research U.K. revealed a confidence gap among physicians when us- ing nonroutine diagnostic tests. The results showed greatest access and clinical confidence in the inter- pretation of MRI scans, while PET scans and CSF tests have the least access and the least confidence in interpretation. This creates a cycle where physicians may hesitate to champion the integration of these novel diagnostics or opt out for their early adoption. To drive change, we must prioritize supporting physi- cians in adapting their clinical practices.

Strong public messaging is essential alongside these efforts. Different cultures and ethnic groups have varied perspectives on dementia, presenting unique opportunities and challenges for ensuring universal access to diagnosis. Effective public mes- saging and engagement are crucial for encouraging individuals to recognize Alzheimer’s early signs and symptoms and empowering them to seek assessment.

Moving from pilot, to policy, to practice

The journey towards the most recent breakthrough— an anti-amyloid treatment for Alzheimer’s disease— has been a long and difficult one. Today, however, we stand at a tipping point in dementia research.

Across the globe, pockets of innovation are propel- ling us closer to a reality free from the fear, harm and heartbreak of dementia. Initiatives like the Davos Alz- heimer’s Collaborative Healthcare System Prepared- ness Learning Laboratory Meetings, which invites experts to share progress with their peers around the globe so that all may benefit from learnings, will serve as invaluable conduits for sharing insights, identifying trends, and fostering a community of best practices as new dementia treatments reach patients.

For the first time, genuine hope permeates the field. While we acknowledge significant challenges and uncertainties, we also see tangible opportunities to begin transforming the lives of those affected by dementia. In the midst of it all, we must seize this chance and ensure that our global healthcare sys- tems are poised to embrace this new era.

Hilary Evans is chief executive of Alzheimer’s Research U.K. Professor Sir John Bell is a professor of medicine at the University of Oxford.

SCIENTIFIC AMERICAN CUSTOM MEDIA 67

[ INFOGRAPHIC ]

The Approaching Alzheimer’s Wave

Dementia is on the rise in every region of the world, with vast implications for public health.

By 2050 more than 150 million people worldwide will suffer from some kind of dementia. (Today that number is more like 50 million.) The increase has two major drivers—in some regions, such as sub-Saharan Africa, the wave comes from population growth. In others, such as China and East Asia, dementia is expected to increase as the population ages. But everywhere, researchers write, “growth in the number of individuals living with dementia underscores the need for public-health planning efforts and policy.” The data here track general dementia instead of Alzheimer’s specifically, in part because dementia is more consistently diagnosed worldwide. Here’s where researchers expect the most cases of dementia to emerge. —KP

KEY

The global map represents the total number of dementia cases expected worldwide by 2050, broken down by region.

About the data

This map depicts numbers from the Global Burden

of Disease study, a comprehensive worldwide effort to quantify the causes of human disability and mortality.

North America

2050: 13.7 million cases 2019: 6.5 million cases

Bar height shows dementia counts in the region.

Predicted number of cases in 2050

Estimated number of cases in 2019

Dots tally the number of cases per 1,000 people—a measure of the disorder’s relative prevalence.

20 cases per 1,000 people

The dementia rate

(cases per 1,000 people) also represents the disorder’s burden on

the community—in

regions with more per- capita dementia, more citizens will need to take on caregiving roles.

Central & South America

2050: 11.8 million cases 2019: 3.9 million cases

Source: E. Nichols et al., The Lancet Public Health, 7, e105–E125 (2022)

68 THE NEW AGE OF ALZHEIMER’S

China and Taiwan

2050: 46.9 million cases 2019: 15.6 million cases

Western Europe

2050: 13.6 million cases 2019: 7.9 million cases

North Africa & Middle East

2050: 13.8 million cases 2019: 3.0 million cases

Types of Dementia

Dementia is a disorder that can be caused by several different diseases, most often Alzheimer’s. A specific diagnosis can be elusive, especially in places with a less Westernized medical culture. Therefore, worldwide data often track dementia instead, as seen here. Here are dementia’s major causes:

Sub-Saharan Africa

2050: 7.8 million cases 2019: 1.8 million cases

Alzheimer’s disease

60–80% of dementia cases

Vascular dementia

20–30% of cases

Frontotemporal dementia

10–15% of cases

Lewy body dementia

10–25% of cases

Source: “Alzheimer’s Disease and Other Dementias,” Mayo Clinic, 2020.

Northern Eurasia

2050: 10.7 million cases 2019: 5.3 million cases

East Asia

2050: 18.4 million cases 2019: 8.2 million cases

South Asia

2050: 15.1 million cases 2019: 4.9 million cases

Oceania

2050: 1.03 million cases 2019: 0.44 million cases

SCIENTIFIC AMERICAN CUSTOM MEDIA 69

Lessons from Around the Globe Community-based programs are exploring new ways of managing Alzheimer’s care.

A Gentle

Sleight of

Hand

The city of Volta Redonda in Brazil has built a model day-care center for Alzheimer’s patients.

BY MAC MARGOLIS

Patrons of the Synval Santos Day Center waiting at the “bus stop.”

arbored patio. There, they sit, chat and reminisce about childhood and the old days, until the panic subsides, as they wait for a bus that never comes.

Years of trial and error have taught Freire’s team of 22 caretak- ers at Synval Santos how to man- age sundown syndrome—a pique of late afternoon distress or the sudden urge to flee that is com- mon to Alzheimer’s patients. Nim- ble intervention, one-on-one atten- tion, patience, and a gentle sleight of hand is the routine for the facil- ity’s 75 elderly patrons, who have moderate stage Alzheimer’s. (At the facility, which is part of the Davos Alzheimer’s Collaborative’s Healthcare System Preparedness Program, patients come for the day and go home in the evenings.)

“If you show concern, stay calm, and never argue,” Freire told me on a recent visit to the Center, “the stress passes, and even those anxious to flee soon forget their troubles.”

Brazil is a country the size of a continent, with staggering in- equalities, where the wealthy enjoy world-class private health services and the poor languish at under- staffed public hospitals. Synval Santos Day Center, however, is a rare exception in Latin America: a publicly financed and managed social service that works.

The institution’s decade-long record of caring for those with Alz- heimer’s is already a beacon for Brazil and elsewhere. Its success makes it a magnet for people from surrounding towns and even out of state.

n some days, wor- ries can cloud the typically upbeat mood at the Syn- val Santos Day

Center, a modest care facility for the elderly with Alzheimer’s disease, in Volta Re- donda, the old steel town 60 miles west of Rio de Janeiro. But Dani-

elle Freire knows just what to do. Freire, a psychologist and the center’s coordinator, takes the an- guished “patron” (no “patients” here, please!) by the arm and coaxes her (8 of 10 clients are fe- male) to the faux “bus stop” in an

70 THE NEW AGE OF ALZHEIMER’S

IMAGES COURTESY OF SYNVAL SANTOS DAY CENTER

Volta Redonda, however, is

lions, even as the central govern- atypical. It is one of just 106 towns

ment downplayed the contagion among Brazil’s 5,568 municipali-

and dismissed the advice of public- ties to provide no-fee services—

health experts.

workshops, exercise and cognitive

But SUS is plagued by chron- calisthenics—for the elderly. The

ic underfunding, red tape and city boasts Brazil’s first and per-

patchy services that vary accord- haps its only public center dedi-

ing to the agendas of local officials cated to Alzheimer’s. It’s much

and national political class.

the same across Latin America,

Volta Redonda was different. A where the number of people with

group of forward-looking city offi- dementia is expected to soar from

cials, social workers and residents 7.8 million in 2013 to more than

in the city were inspired by a lo- 27 million by 2050.

cal dentist, whose wife struggled Many poor nations have is-

for years with Alzheimer’s. They lands of excellence in medicine

saw dementia as a social emer- and clinical care, but only for the

gency in the making. In 2015, they well-off. Just 25 percent of Brazil-

launched the Center for the El- ians have private health insur-

derly with Alzheimer’s and Family ance and access to top-tier treat-

(the formal name for Synval San- ment. In theory, Brazil’s Universal

tos), financed entirely by the city.

In Volta Redonda, where bud- gets are stretched, creativity helps. Besides the make-believe bus stop, a common tactic in Alzheimer’s therapy, the center has developed a strategyofbuilding“workstations” tailored to individual users.

For instance, Synval’s staff talk about how rekindling memories helped Zequinha, a former shoe- maker (who died in 2022), through some difficult days. “Of course you can go home, but would you mind fixing this shoe first?” a psy- chologist would ask, coaxing him over to a workbench covered with tools. For Luzia, another patron known for her green thumb, it’s the table with potted plants and gardening spades that helps keep her centered. And Luzia and her

Health System (SUS, in Portu- guese) tends to the other three- quarters through a nationwide network of free neighborhood clinics and hospitals. The system proved vital during the pandemic, treating COVID emergencies and administrating vaccines to mil-

“The brunt of the disease burden falls on sons and daughters—especially the daughters. Children often give up their jobs to care for sick relatives. In some homes, the elderly care fortheelderly.”

friends are soothed by a baby doll which each one is allocated to carry, cradle and rock and call by name, as if their own.

Brazil needs more than artful- ness. The country has no national plan or protocols for dementia, and a 2020 bill to launch an Alzhei- mer’s policy is still stuck in Con- gress. An estimated 80 percent of cases of dementia go undiagnosed, and even when patients test posi- tive, confirmation routinely comes late. “There’s a barrier in Brazil to implementing public policy until a problem becomes a crisis,” says Fe- lipe Vecchi, a physician and medi- cal director for Brasil Senior Liv- ing, a private elderly facility.

One obstacle to prioritizing the elderly in low- and middle-income societies is the host of other endemic problems, including tuberculosis,

Synval Santos’s psychologist and coordinator Danielle Freire helps to celebrate Carnivale at the day-care center.

SCIENTIFIC AMERICAN CUSTOM MEDIA 71

yellow fever, HIV/AIDS and den- gue—which compete for atten- tion and resources. As a chronic disease, with gradual onset, Alz- heimer’s is easy for politicians to ignore or shortchange come bud- get time. With the share of Brazil- ians aged 65 and over set to grow 488 percent by 2065, they do so at their peril.

Compounding the crisis is a lack of research on dementia (Latin America accounted for just 6 percent of global clinical trials in 2020) and shortage of resources for screening (there’s a wait period of up to six months for PET scans), which leave patients behind and policymakers with too little data. Families and neighbors become first responders of the dementia epidemic, with knock-on effects across the economy.

“The secondary cost of Alz- heimer’s is enormous,” says Otelo Corrêa dos Santos Filho, a psychia- trist in Brazil who works with the Davos Alzheimer’s Collaborative. “The brunt of the disease burden falls on sons and daughters—es- pecially the daughters. Children often give up their jobs to care for sick relatives. In some homes, the elderly care for the elderly.”

As age-related diseases such as Alzheimer’s spread, so will the social fallout. “By failing to make aging and cognitive decline a na- tional priority, we put the welfare of the elderly at risk but also their families and household savings,” says Renato Veras, director of the Open University for Senior Citizens, an annex of the State University of Rio de Janeiro.

Unless planners and policy- makers can overcome inertia and acute political shorterm-ism, Bra- zil’s intrepid family caretakers will need caretakers themselves.

Mac Margolis is a freelance writer based in Rio de Janeiro.

Preaching Brain Health to Young and Old Alike

Scotland is putting in place the infrastructure for preventing Alzheimer’s.

BY WILLIAM UNDERHILL

t’s never too early to start maintaining good brain health. That is the message Alzheimer Scotland is sending to children as young as eight, I

with advice on diet, exercise and keeping up a social life, pack- aged in online material with eye-

catching graphics—and, indirectly, to their parents as well. “The chil- dren can be a very good catalyst for conversation in the home and so raise awareness,” says Jim Pear- son, the nonprofit’s policy director.

The imaginative approach is typical of Scotland, which increas- ingly sees itself as a world leader in the field of dementia care, pre- vention and research. Thirteen years ago, the Scottish govern- ment brought out its first national dementia strategy. Since then, it has followed with three more, the latest in 2023. The Brain Health

72 THE NEW AGE OF ALZHEIMER’S

Children in Scotland are being taught how to keep their brains healthy with good exercise and diet habits and an active social life.

SOPHIE FRASER

Scotland initiative, which distrib- utes the brochures to schoolchil- dren, has the support of the gov- ernment, prominent academics and Alzheimer Scotland.

In its dementia strategy, Scot- land promises every person who has Alzheimer’s a minimum of one year’s support from a named caregiver after diagnosis. A net- work of dementia resource cen- ters spans the country. And an Alzheimer’s phone helpline has been running since 1989. With an eye to publicity, last year Brain Health Scotland launched a clinic at Murrayfield, the home ground of Scotland’s rugby team in Edin- burgh, where former players go to get regular brain checkups. The National Health Service (NHS) hopes to set up a chain of similar clinics nationwide by 2025.

About 90,000 people in Scot- land have dementia. It is one of the country’s leading killers, with a death rate similar to coronary heart disease. Government au- thorities have come to recognize the role of lifestyle factors in con- tributing to the disease, as well as the importance of early diagnosis. Together with a new generation of drugs that slow the progress of Alzheimer’s, experts reckon that reducing exposure to 12 key risks, such as diabetes or alcohol con- sumption, can delay or prevent 40 percent of dementia cases.

Researchers have access to a vast pool of anonymized data in the centralized healthcare system of the NHS. Scotland can also lay claim to its own particular tradi- tion of medical record-keeping. As far back as the 1930s, it launched a unique survey testing the intel- ligence of the nation’s children. The performance of almost all those born in 1921—more 80,000 in total—was logged, creating a useful reference resource for pop- ulation studies.

The spirit of cooperation among the main stakeholders is crucial. For instance, the Univer- sity of St Andrew’s, the country’s oldest university and the alma mater of Prince William, has twice in the last two years hosted inter- national brain-health summits, bringing together leading figures from what’s called the “triple he- lix” of universities, healthcare providers and the commercial life sciences sector. “What is unique in Scotland is the level of collabo- ration,” says Pearson.

Such joint efforts hold out the promise of commercial dividends. Frank Gunn-Moore, an expert in neurodegeneration at St An-

“Early diagnosis will be transformative in the way we assess, manage and con- ceptualize clinically Alzheimer’s disease.”

drew’s—whose recent work on the brains of stranded dolphins made headlines by revealing that their brains showed some of the classic markers of human Alzheimer’s—is seeking to create a government- backed fund that would help form spin-out companies from all Scot- tish universities working on Alz- heimer’s and dementia. “Drug companies really want to work in Scotland because it’s manage- able,” says Gunn-Moore. “We are ambitious: we really want to go big scale.”

It’s happening already. Ear- lier this year the healthcare giant Roche Diagnostics announced a partnership with Scottish Brain Sciences (SBS), an Edinburgh- based research institute, to ex-

plore the earliest biological signs of neurodegenerative disease us- ing blood-based biomarkers. “Ear- ly diagnosis will be transformative in the way we assess, manage and conceptualize clinically Alzheimer’s disease,” says Craig Ritchie, the firm’s founder and CEO, who has emerged as a central figure in the world of Alzheimer’s research and prevention. The selection of SBS for the project was a “huge vote of confidence in the Scottish life sci- ences sector.”

Disillusioned by the bureau- cracy of the NHS and the lengthy delays facing patients waiting for appointments at memory clinics, SBS is now rolling out its own net- work of dementia-prevention re- search centers across Scotland. On offer will be free access to the lat- est diagnostic tests and medica- tion through big drug trials funded by the pharmaceutical industry. In Ritchie’s words: “We are ready for this next generation of treatments to start. The problem is the infra- structure is not in place to do it.”

Scotland is one of six countries participating in a pilot program, funded by the Davos Alzheimer’s Collaborative, that is making new blood tests and digital cognitive assessments available to Alzhei- mer’s patients. “We have a proud history of being at the forefront of dementia policy, of being half a step ahead of others, so it follows naturally that there’s interest in research,” says Wendy Chambers, a dementia consultant working on the trials.

Who knows where that will ultimately lead? Chambers says: “It might not change much for my generation, but it certainly starts to change what the progression of the disease looks like for future generations.”

William Underhill is a freelance writer based in Oxford, U.K.

SCIENTIFIC AMERICAN CUSTOM MEDIA 73

It Takes a Village

Community leaders in Kenya are increasing awareness of Alzheimer’s and reducing the stigma.

ABY APRIL REESE

few years ago,

people are no longer pushing it under the rug and saying, ‘there’s men- tal health re-

nothing we can do about it,’” says searcher Christine

Musyimi traveled

Mutunga, who was a coauthor, with Musyimi, of a 2021 study re- to rural Kenyan

porting the work. “There’s a bet- villages to investi-

gate how people perceived demen-

ter understanding of the condi- tia. She made some disconcerting

tion now.”

To combat misperceptions about Alzheimer’s, in 2022 ADOK, the Kenya Ministry of Health and others teamed up to create the STRIDE Kenya initiative. (STRIDE stands for Strengthening Re- sponses to Dementia in Low and Middle Income Countries.) Based on input from dementia patients and their caregivers, the idea is to get more people talking about Alzheimer’s disease. “We know the most effective way to reduce stigma is through social contact,” says Sara Evans-Lacko, a mental health services researcher at the London School of Economics and Political Science who worked on an anti-stigma toolkit the STRIDE Kenya team developed.

The toolkit, called “Don’t For- get I’m Human,” includes an inter- vention how-to for caregivers and clinicians. The centerpiece of the approach is to gather caregivers, show them videos of people with dementia, and then hold a discus-

discoveries. Some people thought that dementia was simply part of the aging process. Others had nev- er heard of Alzheimer’s or thought it was strictly a Western disease. Still others thought people show- ing symptoms of dementia were cursed and were being punished by the gods.

Today it’s another story. “We’ve come from very far,” says Eliza- beth Mutunga, a psychotherapist who founded Alzheimer’s and Dementia Organization Kenya (ADOK), a Nairobi-based nonprof- it advocacy and research group, and has worked to educate peo-

ple about dementia. “It took a lot of knocking on doors, but now

An estimated 87,000 people in Kenya have some type of demen- tia. By 2050, the number of cases is projected to rise to 361,000—a 315 percent increase—driven primar- ily by population growth. But be- fore ADOK’s work, misperceptions about dementia have kept many people in Kenya, a largely rural na- tion of 55 million people, from get- ting the care that they need.

“The combination of poor awareness and ill-equipped health- care systems leads to stigma manifested in the form of patchy diagnostic pathways, neglect and abuse,” Musyimi, Mutunga and their co-authors wrote in their 2021 study.

COURTESY OF ADOK

74 THE NEW AGE OF ALZHEIMER’S

“We’ve come from very far. It took a lot of knocking on doors, but now people are no longer pushing [Alzheimer’s] under the rug and saying, ‘there’s nothing we can do about it.’ There’s a better understanding of the condition now.”

mentia at the same time as other conditions, such as diabetes. The project, which is funded by the Davos Alzheimer’s Collaborative (DAC) and is the first of its kind in Kenya, screened 3,500 people in rural areas for six months. It found dementia in about 18 per- cent of cases.

The team is now trying to se- cure funding to determine wheth- er the trainings led to increased access to care. Mutunga believes they’ll find that it has. “Once peo- ple have understanding, then a lot of people actually come in to get care,” she says.

The challenge now is to scale up these efforts and make screen- ing, care and support the norm and not the exception. Kenya’s Minister of Health Simon Njugu- na told a June 21 virtual meeting on healthcare system prepared- ness, convened by DAC: “We’re very keen to develop a national plan on dementia.”

So far, Alzheimer’s advocates have made “great progress in terms of the policy impact,” says Evans-Lacko. “So don’t give up,” Mutunga says. “Keep pushing. Eventually the door will open.”

April Reese is a freelance writer based in Aveiro, Portugal.

sion in which caregivers share their thoughts and personal expe- riences. Participants are encour- aged to reflect on how they can support the people with dementia they are helping take care of. “It’s really trying to humanize people with dementia, to build empathy,” says Evans-Lacko..

Building trust among caregiv- ers is an important component of the approach. “We didn’t want to just go in and start telling them about dementia,” says David Ndetei, a professor of psychiatry

at the University of Nairobi who helped design the intervention. “We went right to the families, and we asked them a simple ques- tion: Do you see people who seem to forget sometimes?” That start- ed a dialogue based on mutual re- spect, he says.

The next step after education is to find ways of delivering care. To that end, Musyimi spearheaded the DEM-SKY project, an initiative to train community healthcare workers in rural Makueni County in screening people over 60 for de-

Building trust among caregivers is an important part of nonprofit ADOK’s approach in Kenya.

SCIENTIFIC AMERICAN CUSTOM MEDIA 75

Teaching Good Brain Hygiene

In Japan, where more than 90,000 people are 100 years or older, clinicians are advocating lifestyle habits that reduce the risk of Alzheimer’s.

HBY MIHOKO IIDA

isatomo Kowa is not waiting around for new drug treat- ments for Alzhei- mer’s. He is already exploring preventive

measures, including changing fun- damental lifestyle habits before the onset of the debilitating disease.

“Once a patient is diagnosed with the disease, there are drugs to treat the symptoms. But the disease itself cannot be cured,” says Kowa, a neurologist and di- rector of the Dementia Preventing Center at Kobe University Gradu- ate School of Health Sciences. “So how can we prevent or delay the onset at an earlier stage?”

Since 2019, Kowa has been leading a program, called Cogni- care, at Kobe University. It empha- sizes the importance of educating the public on leading a balanced lifestyle that cares for and boosts brain function, including healthy eating habits and exercises that mix mental tasks with physical ones. “If we are all living to be 100

years old, we should all be more mindful of brain health from an early age,” he says.

Kowa’s view reflects a com- mon societal attitude towards ag- ing and mental health in Japan, which currently has one of the oldest populations in the world. In 2021, the average lifespans were 81.5 years for men and 87.6 years for women, according to govern- ment statistics. With many people living to well over 100—Japan had more than 90,000 centenarians in 2022—the number of people being diagnosed with Alzheimer’s dis- ease and other forms of dementia is on the rise. The Health Ministry estimates approximately 7 million will be diagnosed with dementia in 2025, up from 4.62 million in 2012. “People need to change their lifestyle habits beginning in their 40s because the brain begins to change roughly 20 years before the onset of dementia,” he says.

Cognicare aims to teach peo- ple good brain hygiene. For the equivalent of $40 per month, each

76 THE NEW AGE OF ALZHEIMER’S

Gerontology, based in Aichi Pre- fecture, instructors and caregivers proselytize on social media plat- forms, including Instagram and YouTube, where they demonstrate fun and creative ways to stimulate the brain while exercising, includ- ing word games, counting back- wards while walking and clapping your hands while stomping your feet. The exercises often focus on focusing the mind on one task while the body performs another. The goal is not to get better at both tasks but rather to tax the brain and the body simultaneously.

“The exercises are actually complex and difficult to do,” says Mie Nishihama, a caregiver and occupational therapist at Shigei Hospital in Okayama Prefecture, who has been overseeing classes offered by the hospital’s culture and fitness arm, Harmony Kura- shiki, since 2019. “But what’s important is for the exercises to be done in groups so that par- ticipants have people to laugh with when they make mistakes.”

“We are all at risk of dementia as we age. And there is no single answer to prevent this. It’s not just about nutrition, or exercise, but it’s about leading a balanced lifestyle starting early and continuing for as long as possible.”

participant gets a basic medical checkup; attends health-related seminars, including information on nutrition; and takes part in “cognicise” exercise classes (avail- able physically or over video-con- ferencing). The program has at- tracted participants from 40 to 90 years old, with most in their 70s.

Cognicare has garnered much media attention. Created by the National Center for Geriatrics and

She stresses the importance of a communal connection, especially among the elderly. The program does not collect data on how much patients improve from the exercises.

Yuka Ota, a certified instruc- tor of cognicise in Shizuoka Pre- fecture, says that teaching elderly people is “similar to running up a down escalator.” She has been teaching classes at various facili-

ties since 2016. Her impression

Preparedness Program. He hopes

cognitive, and physical activity) is that while it is hard to see

the study’s results will contribute

may prevent or delay up to 40 per- her students making significant

to the development of dementia-

cent of dementia.

improvements, she knows from

prevention measures in Japan.

“Alzheimer’s disease is not experience that “sustaining the

To better educate the public on

something that happens suddenly. status quo [in health and cogni-

brain health, Kowa also recently

This is why it’s important to have tion] takes a tremendous amount

published a nutrition book for a

a comprehensive program such as of effort.”

general audience. The title trans-

Cognicare to check for early signs Kowa is currently working on

lates from the Japanese roughly

so that medical professionals can the final analysis of the effects of

as: “Eighty is not too late to start.

better guide patients to minimize

KOBE UNIVERSITY

a separate multifactorial interven- tion aimed at preventing demen- tia. Specifically, he and his group are exploring the significance of two new methods for the early detection of Alzheimer’s disease: a digital cognitive assessment tool, and a tool to estimate the presence of amyloid in the brain

using blood-based biomarkers, as part of the Davos Alzheimer’s Collaborative Healthcare System

How to eat to keep dementia away: The complete guide.” The book introduces foods, such as some types of fish, that are good for the brain and warns against lack of sleep, as well as smoking. He also cites in the book the 2020 report of the Lancet Commission on De- mentia Prevention, Intervention, and Care that states modifying 12 risk factors (including the lack of education, nutrition, and social,

the deterioration as much as pos- sible,” says Kowa. “We are all at risk of dementia as we age. And there is no single answer to pre- vent this. It’s not just about nu- trition or exercise, but it’s about leading a balanced lifestyle start- ing early and continuing that life- style for as long as possible.”

Mihoko Iida is a freelance writer based in Tokyo.

When exercise is done in groups, participants have a chance to laugh at their mistakes and build communal connections.

SCIENTIFIC AMERICAN CUSTOM MEDIA 77

Taking It to the Streets

In Armenia, clinicians travel the countryside in a minivan, offering tests for Alzheimer’s.

ABY APRIL REESE

rax Vartevanian started forgetting names and dates in 2017, but she wasn’t diagnosed with Alzheimer’s until last year, when a neurologist ordered a brain scan and blood test. By then, she had developed a

tendency to repeat a question over and over. Her husband, Gegham, grew increasingly frustrated try- ing to get her to stop, to no avail.

Recently, though, Gegham learned a crucial piece of informa- tion that helped him cope with his wife’s illlness: “Repeating stories or asking questions over and over again are symptoms of [Alzhei- mer’s] disease and are not inten- tional,” he read in a guide for care- givers. Now, he says, when the same thing happens, he usually gives in.

Helpful advice for Alzheimer’s caregivers has not been common- place in Armenia. The former So- viet republic, with a population of 2.8 million at the crossroads of Europe and Asia, has largely neglected its dementia patients, because of a lack of awareness of the condition and stigma. But the country has made consider-

able progress, in part because of the work of NGOs such as Al- zheimer’s Care Armenia (ACA),

which in 2021 began distributing

score better on their assessment 10,000 caregiver’s guides to clini-

test” after participating in the cians and patients—the guide that

programs, she says.

proved so helpful to the Varte-

For people with more ad- vanians. The ACA, with funding

vanced dementia, ACA started from the Davos Alzheimer’s Col-

laborative (DAC) and other orga-

78 THE NEW AGE OF ALZHEIMER’S

nizations, has put in place several initiatives designed to bring medi- cal and psychological support to Alzheimer’s patients.

Jane Mahakian, a gerontologist who lives in the U.S., founded ACA in 2017 after she noticed, during her decades of trips to Armenia, that many people lacked an aware- ness of Alzheimer’s. She organized the country’s first Alzheimer’s conference in 2018, and, to her surprise,morethan400peopleat- tended.“Thatwasapivotalpoint in our efforts to start creating vis- ibility and just get people to start thinking about cognitive impair- ments not only for older adults but for all adults,” she says.

Building on that momentum, she collaborated with Mission Armenia, an NGO that provides meals and other support to the el- derly, to establish two “healthy ag- ing memory clubs,” where people with mild to moderate memory challenges can engage in activi- ties that promote brain health, such as playing games, socializ- ing, and making music and art. At these clubs, held at the Mission Armenia facility in Yerevan, psy- chologists lead movement therapy sessions, give classes on educa- tion and nutrition, and conduct tests every three months to track participants’ cognitive abilities. “Those small programs were actu- ally very instrumental in building up the awareness and visibility withinthecountry,”shesays.(Two other NGOs, Mission Armenia and Oron, now oversee the groups.)

Participants are tested every three months to track changes in cognition. “We have seen people

a memory cafe in October 2022. Weekly gatherings, led by a psy- chologist and a social worker, of- fer a safe space for people with dementia to engage in cognitive exercises and games over coffee and snacks and for caregivers to get support. “It’s a happy place for them,” says Mahakian. “It’s a way to connect. For many of them, this is really the only place where they feel a sense of belonging.”

To reach more people who may need Alzheimer’s care, Mahakian got the idea to create a mobile clinic in a minivan that would travel the country with a team of clinicians. She partnered with Ar- menian EyeCare Project, a mobile clinic for eye care that had already

ALZHEIMER’S CARE ARMENIA

been conducting exams and per- forming surgeries. Beginning in June 2022, ACA’s healthcare pro- viders have been following the EyeCare vans and providing de-

that runs the mobile screening unit, also provides training to healthcare providers at hospitals and clinics around the country in recognizing signs of dementia.

lation of researchers is working to strengthen dementia research ca- pacity. Under a new project called COBRAIN Armenia, Yerevan State Medical University, with input from advisors from across Europe and the U.S., is exploring new ways to treat and prevent chronic brain disorders, including Alzheimer’s disease.

Zaven Khachaturian, presi- dent of the Campaign to Prevent Alzheimer’s Disease, who serves as an advisor on the project, says it could play an important role in improving care for people with not just dementia, but other brain disorders as well. “It would benefit not only Armenia, but it would be a prototype for building a next-generation healthcare sys- tem for chronic brain disorders,” he says. Khachaturian is Arme- nian, but lives in the U.S., and served as associate director at the U.S. National Institute on Aging from 1977 to 1995.

In March, as part of a wider World Health Organization ini- tiative, Armenia began drafting a national dementia plan. Although details haven’t been released, Ma- hakian would like to see the gov- ernment mandate screening for dementia by physicians during annual checkups.

Key to improving care, she says, is strengthening coordination be- tween NGOs, researchers and the Armenian government. “We’re re- ally working on developing these multilevel partnerships to not only create sustainability for our early detection screening program that we have been very successful with but also to develop better ways to get people care,” she says. “How do webestmeettheirneedsandtreat them? We really need to think out- side the box.”

April Reese is a freelance writer based in Aveiro, Portugal.

Activities such as crafts, games and music promote healthy brains. Below: a memory cafe run by Alzheimer’s Care Armenia.

“It’s a happy place for [patients]. It’s a way to connect. For many of them, this is really the only place where they feel a sense of belonging.”

mentia screening to their clients. “Partnering with them was very important” for getting buy-in from both patients and healthcare practitioners, she says. “It took the fear out of the disease.”

The Brain Health Armenia Project, a DAC-funded program

In May 2023, the project began providing in-home care to Alzhei- mer’s patients as well.

ACA has also tried some uncon- ventional strategies for spreading awareness and improving care. The organization teamed up with a ro- botics expert, Karen Khachikyan, to develop “Robin the Robot,” a dementia companion deployed at the Nork Old Age Home in Yerevan. Studies found that Robin the Robot helped alleviate loneliness and iso- lation and improve cognitive ability oftheresidents.ACAalsostarteda national radio show on the coun- try’s public radio network to show- case “older adults leading positive lives,” says Mahakian.

A small but ambitious constel-

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“We’re at a tipping point with Alzheimer’s”

Bill Gates talks about his own experience as a caregiver and what needs to be done to fight this disease.

It would be hard to imagine any one person who’s had more of an impact on public health than Bill Gates. Much of the wealth he amassed as founder of Microsoft has gone to charity—according to Fortune, he is one of only five bil- lionaires to have given away more than 20 percent of his wealth. In

2023, the Bill and Melinda Gates Foundation, which he started with his former wife, Melinda Gates, spent more than $8 billion of its more than $70-billion endowment.

Gates has focused his philan- thropy largely on some of the most intractable health problems, such as malaria, HIV/AIDS and child- hood vaccination. In recent years, he has turned to Alzheimer’s dis- ease, starting with diagnostics and more recently expanding to proteomics and healthcare pro- grams related to the disease. Sci- entific American Custom Media asked him about Alzheimer’s:

SCIENTIFIC AMERICAN CUSTOM MEDIA:

What sparked your interest in Alzheimer’s? How has your personal experience with the disease contributed to your decision to get involved?

GATES: Like many people, I have a personal connection to Alzheimer’s. My dad died from Alzheimer’s, so I understand first-hand what a cruel disease it is, and how diffi- cult it can be to watch a loved one suffer with it. We were fortunate to have the resources to provide my dad with excellent care, and our

TONY HEALEY

80 THE NEW AGE OF ALZHEIMER’S

If we’re able to catch the disease sooner, we’ll be able to give patients more options for treatment, social services and participating in clinical trials.

familyisgratefulforthewonderful caregivers who helped him in the 13 years he lived with the disease. But for the majority of families battling Alzheimer’s, this is not an option. Caregiving most often falls to a spouse or a child, which can be overwhelming.

The financial burden of the dis- ease is easier to quantify than the emotional cost. The lifetime cost of care for Alzheimer’s and other dementias is rapidly increasing in the U.S., Japan, Europe, and other countries. According to the Insti- tute for Health Metrics and Evalu- ation, the global cost will exceed $1.6 trillion by 2050 and represent nearly one-third of all healthcare spending. Unlike those with many chronic diseases, people with Alz- heimer’s incur long-term care costs as well as direct medical expens- es. If you get the disease in your 60s or 70s, you might require ex- pensive care for decades.

As I spent time learning about Alzheimer’s and the research into it, I came to understand the chal- lenges. The brain can’t be sampled easily or often, for example, and the blood-brain barrier is a dou- ble-edged sword—it both protects the brain and makes it harder for treatments to get in.

Even so, as I learned about all the innovation in this field, I grew optimistic about the ability to make progress toward treatment and eventually a cure. This is a frontier where we can dramatically improve human life. It’s a miracle that peo- ple are living so much longer today, but longer life expectancies alone are not enough. People should be able to enjoy their later years—and

weneedabreakthroughinAlzhei- mer’s to fulfill that.

As someone who takes a bird’s- eye view of major health issues, how would you describe the current outlook for Alzheimer’s research and clinical practice?

After decades of negative clini- cal trials and dozens of failed therapies, researchers are making progress on both diagnostics and therapeutics.

Blood-based diagnostics are advancing rapidly—the first blood test for Alzheimer’s, PrecivityAD, was launched in late 2020. A few

The therapeutic pipeline is diverse and robust.

others have followed since, but we are looking forward to the first FDA-cleared blood tests on the horizon. Once this becomes a real- ity, the next hurdle will be ensur- ing these tests are used properly, accessible and available to the pa- tients that need them, and that we understand how these tests work in different patient populations.

The therapeutic pipeline is diverse and robust—at the begin- ning of 2023, there were 187 trials assessing 141 different therapeu- tics. The anti-amyloid agent lec- anemab has been approved for use in patients, and donanemab is ex- pected to follow soon. Other ther- apeutics in the pipeline include

disease-modifying therapies and cover a wide range of approaches, including amyloid and tau but also newer mechanisms such as neuro- inflammation, synaptic plasticity/ neuroprotection, metabolism and oxidative stress (see J. Cummings et al., Alzheimers Dement (N Y), Apr-Jun 2023, Vol. 9: e12385).

With these and other break- throughs that are coming, it’s fair to say we’re at a tipping point on Alzheimer’s.

In recent years you’ve directed funding to accelerate develop- ment of diagnostic technologies for Alzheimer’s. Why did you pick that particular area to start?

We systematically looked at the barriers to R&D on Alzheimer’s disease, and we heard consistent- ly that not having a simple, non- invasive, scalable and relatively inexpensive diagnostic (such as a blood test) was a key challenge. It’s a barrier to early diagnosis and subsequent enrollment in clinical trials—and continuing to make advances on the disease de- pends on getting enough people enrolled early enough in trials.

Another problem is that the commercial market for diagnos- tics does not stimulate invest- ment, so potential scientific break- throughs are not being pushed forward as rapidly as they should be. This is why I partnered with the Alzheimer’s Drug Discovery Foundation to create the Diagnos- tics Accelerator, which is designed to advance bold ideas for easier, more accurate and earlier diagno- sis of Alzheimer’s disease.

SCIENTIFIC AMERICAN CUSTOM MEDIA 81

Do you have any plans to direct funding to accelerate progress in other areas of Alzheimer’s, such as treatments, diversity in clinical trials, public-health outreach or others?

We’re focused on five a reas: u n- derstanding the biology of the disease, diagnosing it, treating it, overcoming bottlenecks in clini- cal trials, and making it easier for researchers to share data with each other.

One of our latest investments is with the Global Neurodegen- eration Proteomics Consortium, which brings together data from more than 40,000 blood samples around the world so research- ers can identify biomarkers for detecting neurodegenerative dis- eases and identifying new mecha- nisms to test. We’re also partners in the Clinical Trial Recruitment Lab and the Global Alzheimer’s Platform Bio-Hermes Study, both of which are aimed at recruiting people from diverse backgrounds to join clinical trials.

We’re also partnering in the Davos Alzheimer’s Collaborative’s Healthcare System Preparedness Initiative, as well as a recently announced Innovative Health Initiative-funded program, AD- RIDDLE, all of which are efforts to ensure that breakthroughs can be deployed in healthcare systems once they’re approved for use.

You’ve written about how data sharing is vital to learning more about Alzheimer’s disease and accelerating progress. Why is that so important and how is that effort going?

Over the past few decades, drug trials and longitudinal cohort studies have generated an enor- mous amount of data. But right now, that information is not being

shared to the fullest extent pos- sible. Much of it remains locked away or accessible only to select groups. That’s a missed opportu- nity as well as a disservice to the people who agreed to join studies so they could help advance the field.

To help unlock these datasets while making sure they’re used re- sponsibly, we worked with several partners to launch the Alzheimer’s Disease Data Initiative. Our goal is to help researchers from around the world access more informa-

People should be able to enjoy their later years—

and we need a breakthrough

in Alzheimer’s to fulfill that.

tion by making data and data plat- forms interoperable. So far, the effort has established interopera- bility with several data platforms, including the Dementias Platform U.K. portal, the Vivli Platform, and the Global Alzheimer’s Asso- ciation Interactive Network plat- form (GAAIN).

More recently we’ve gotten in- volved in the European Platform for Neurodegenerative Diseases (EPND), which is building a plat- form that will help researchers make their data and biosamples shareable. Their platform will build on data and analysis tools made available by the Alzheimer’s Disease Data Initiative, including the Global Research and Imaging Platform, a nonprofit that I fund. Finally, we’ve created a two-year fellowship, named after my dad, that brings in researchers from

around the world to work on data analysis and to champion the idea of interoperability.

What is the biggest obstacle to making progress on Alzheimer’s? Is there a cultural shift that needs to happen?

Although we’ve recently seen im- portant advances in therapeutics and diagnostics, there is still a lot we don’t know about Alzheimer’s disease and the brain. Timely diagnosis is the first major shift that needs to happen—many stud- ies have shown that Alzheimer’s disease and dementia are dra- matically underdiagnosed today. If we’re able to catch the disease sooner, we’ll be able to give pa- tients more options for treatment, social services, and participating in clinical trials and other re- search opportunities.

But Alzheimer’s disease is also a heterogeneous disease, and patients who have it show a wide range of pathologies in the brain and resulting symptoms. I’m hopeful that the field will be able to capitalize on recent ad- vances in diagnosis and treat- ment—and also make it easier and more efficient for people to enroll in Alzheimer’s clinical trials—so we can continue to improve our understanding of subtypes of the disease and target our efforts at treatment and prevention.

Finally, there is still a lot of stigma surrounding neurodegen- erative diseases. That makes it harder to discuss them openly. But I think a lot of that is driven by the fact that these diseases seem so mysterious because we haven’t had sophisticated diagnostics or treatments. I’m optimistic that as more advances happen, the stig- ma will fade, and open public con- versations about Alzheimer’s will accelerate progress even more. ■

82 THE NEW AGE OF ALZHEIMER’S

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SCIENTIFIC AMERICAN CUSTOM MEDIA 83

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