Treatment and care for people with AD should be individualized based on symptoms and social situation.

The first step following diagnosis is to provide education, support, and resources to the patient and the family. This news is often devastating and may evoke many questions about the disease process, time course, and potential treatment options. A social worker, psychologist, or other mental health professionals should be made available to provide emotional support and psychosocial input.

A referral should be made to a community service organization, such as the Alzheimer’s Association. Alzheimer’s Association National Institute on Aging: about Alzheimer’s disease – caregiving MedlinePlus: Alzheimer’s caregivers Family Caregiver Alliance resource center Caregiver support groups have been shown to be beneficial to caregivers and should be considered, where available.[102]

The family should be aware that inevitable disease-related deficits will develop in memory, behavior, mood, and function (e.g., incontinence, immobility, confusion). These should be discussed in the context of the current state of disease symptoms.

The benefits and risks of nonpharmacologic and pharmacologic treatments for the cognitive and behavioral features of AD should be discussed with the patient and family, so that informed decisions can be made about the use of these interventions. Treatment will be determined by the symptom constellation of the individual patient and the needs and responsiveness of the caregivers.

If an advance directive or power of attorney for health care has not been prepared, these documents and other end-of-life discussions should take place.

Environmental review

A home safety evaluation should be undertaken, as well as an assessment of transport, driving, and self-care needs by an occupational therapist.[103] [104]

AD is a risk factor for falls and, therefore, fractures, especially in the context of certain medications for behavior and changes in gait.[105] [106] Therefore, an assessment of the risk of falls, and interventions to mitigate the risk, should be incorporated in the home safety evaluation.

Cognitive impairment: pharmacotherapy goals

The major pharmacologic treatment goals are to:

Slow symptoms of disease progression by preserving memory and functional abilities

Reduce behavioral disturbance

Delay entry into institutional care settings.

Although a minority of people will benefit from a noticeable improvement in memory, the majority of responders to pharmacotherapy will achieve only a relative plateau in disease-related symptoms for 1-2 years. Two major classes of pharmacologic treatment are used:

Cholinesterase inhibitors

N-methyl-D-aspartate (NMDA) receptor antagonists.

Both drug classes work by altering the balance of neurotransmitters, which is disrupted in AD due to neuronal damage. Cholinesterase inhibitors and NMDA receptor antagonists may be combined for potentially greater benefits.[108] [109]

Cognitive impairment: cholinesterase inhibitors

Cholinesterase inhibitors should be started at the lowest possible dose and titrated gradually. This is particularly relevant in older patients, who are more sensitive to cholinergic adverse effects, and in those in whom comorbidity may be exacerbated by altered acetylcholine metabolism. Renal impairment and hepatic dysfunction can also affect dosing. The clinical benefit of cholinesterase inhibitors is modest.[107] However, open-label extensions suggest that benefits may continue beyond 1 year with ongoing treatment.[110] [111]

Cholinesterase inhibitors should not be stopped abruptly, as patients may experience rebound worsening of cognition. There is little consensus about when to consider discontinuation of these treatments, and what criteria to use.[112]

Cholinesterase inhibitors for mild to moderate AD

Oral rivastigmine and oral galantamine are approved by the Food and Drug Administration (FDA) for mild to moderate AD.

A once-daily extended-release formulation of galantamine is available and should be considered when compliance or dosing rationalization is an issue.[113]

Cholinesterase inhibitors for mild to severe AD

Oral donepezil and transdermal rivastigmine are FDA-approved for mild to severe AD.[114]

Donepezil has been shown to be beneficial at all stages of the disease.[115] Adverse effects, particularly gastrointestinal, are significantly more common with the higher-dose formulation approved for moderate to severe disease.[116] Increasing the dose to the high end of the dose range may confer only modest benefit.

The rivastigmine transdermal patch may increase compliance and reduce cholinergic adverse effects, and is preferred by caregivers to oral formulations.[117] [118] [119] [120] [121] Patients experiencing adverse effects with oral cholinesterase inhibitors may be transitioned to transdermal rivastigmine therapy without significant complications.[122]

Cholinesterase inhibitor efficacy

One randomized double-blind placebo-controlled trial of community-living patients with moderate to severe AD who had been treated with donepezil for at least 3 months reported cognitive benefits (that exceeded the minimum clinically important difference) and functional benefits from continued donepezil over 12 months.[123] Patients who were assigned to discontinue donepezil and start memantine experienced similar benefits.[123] Donepezil is unlikely to be unique in its effects in late stage disease, but it is the only cholinesterase inhibitor that has been tested and approved in this population.

Pharmacologic treatment with cholinesterase inhibitors was associated with reduced risk of death in one large, community-based observational study.[124] Retrospective data from the UK indicate that cholinesterase inhibitors are associated with a period of cognitive stabilization (2 to 5 months) before a continued decline in cognitive function at the pretreatment rate.[125]

Cognitive impairment: NMDA receptor antagonists

Memantine is indicated in moderate to severe AD, and is widely used off-label for mild AD.[126]

Memantine should be given as a sole treatment if cholinesterase inhibitors are contraindicated, are not tolerated, or have been shown to be ineffective.[127]

Coadministration of memantine with a cholinesterase inhibitor may be considered as the range of AD symptoms increases and the severity of behavioral and psychological symptoms worsens.

NMDA receptor antagonist efficacy

Memantine is well tolerated, and modestly improves outcomes compared with placebo in moderate to severe AD, but evidence suggests no benefit in mild AD.[126] [128] [129] Meta-analyses suggest adding memantine to a cholinesterase inhibitor may modestly improve cognition in people with moderate to severe AD.

Cognitive impairment: nonpharmacologic treatments with limited evidence or no effectiveness

Exercise: meta-analyses suggest that exercise may improve cognition, with aerobic exercise being associated with greatest benefit.[132] [133] An earlier Cochrane review found that exercise did not benefit cognition, but may improve activities of daily living in patients with dementia.[134]

Cognitive stimulation therapy/cognitive training: may improve cognitive function among patients with mild to moderate dementia, but evidence is of low quality.[49] [132] [135] [136] [137] [138]

Occupational therapy: occupation-based interventions, physical exercise, and error-reduction techniques may delay functional decline in people with AD.[139]

Memory aids: may enhance verbal communication between individuals with AD and their caregivers.[140]

Music therapy: reported to moderately improve symptoms of depression, and possibly behavior, emotional wellbeing, and anxiety, in patients with dementia, but with little or no effect on cognition, agitation, or aggression.[141] This is a safe intervention that may benefit some people but not others, so is worthwhile trying clinically.

Reminiscence interventions: may be some benefit, but further research is required.[142] [143]

Validation therapy: insufficient evidence to recommend this intervention.[144] Validation therapy reinforces the reality and personal truth of the affected person.

Cognitive impairment: pharmacologic treatments with limited evidence or no effectiveness

Nonsteroidal anti-inflammatory drugs (NSAIDs): no statistically significant differences in cognition between NSAIDs (traditional or selective cyclo-oxygenase-2 [COX-2] inhibitors) and placebo in community-living people with mild to moderate AD.[145] Gastrointestinal bleeding and cardiovascular adverse effects occurred more commonly in people taking NSAIDs compared with placebo.

Aspirin: insufficient data to determine whether there is a role for aspirin in the management of cognitive decline in patients with AD.

Vitamin E: no evidence that vitamin E given to people with mild cognitive impairment (MCI) prevents progression to dementia, or that it improves cognitive function in people with MCI or dementia due to AD.[146] [147]

Ginkgo biloba: evidence is inconsistent at best.[148] [149] Ginkgo biloba is not routinely recommended because preparations (which are available without prescription) may differ with respect to purity, and concentration of active ingredient.

Behavioral and psychological symptoms of AD

Behavioral symptoms are intrinsic to AD and may become increasingly challenging to manage as the illness progresses. Behavioral and psychological symptoms of AD include:

Anxiety

Agitation

Aggression

Apathy

Wandering

Hallucinations

Delusions

Depression

Insomnia

Dementia-related psychosis.

The management of these manifestations should involve coordination between the caregiver, the family, the physician, and the facility providing care for the patient. Behavioral strategies should be exhausted before considering pharmacologic strategies. It is important to note that behavioral symptoms are associated with rapid progression  and are predictive of nonpsychiatric admissions in this population, although the mechanism of this correlation is unknown.[151]

Behavioral and psychological symptoms management: nonpharmacologic strategies

Families and caregivers should be encouraged to promote independent functioning for as long as possible. Simple measures such as providing a comfortable environment and encouraging social gatherings help patients adjust to their surroundings and lessen anxiety and agitation. Activities such as gardening, vacuuming, and setting the table provide routine and foster a sense of utility.

Measures such as identification bracelets or installing sound and motion detectors make the environment safe for wandering patients and reduce the burden on caregivers. Tagging with devices with global positioning technology has also been proposed and may offer some reassurance to caregivers about the patient’s safety. Alzheimer’s Society: assistive technology

Patients with AD frequently experience insomnia. Measures to keep the patient active and occupied during the day can reduce wakefulness at night time. Other measures such as sleep hygiene, daily walking, and bright light therapy have been shown to improve sleep quality.[152] [153]

Providing a well-structured, calm daily routine helps modulate behaviors such as agitation, delusions, and hallucinations. Actions that can be useful include:

Always explaining the caregiving actions in advance, such as putting clothes on or helping with showering

Giving written instructions whenever possible

Ensuring that comorbid illnesses are appropriately addressed by physician and nursing staff

Ensuring that pain is adequately addressed

Using calendars, clocks, and charts to help patients stay oriented to the time and place

Using lighting to reduce confusion and restlessness at nighttime

Ensuring the environment is safe and removing unnecessary furniture and items that might harm patients if they wander.

Caregiver support and oral counseling should be provided, as this may help delay entry to institutional care settings and reduces depression in the caregiver.[154] [155]

Some functional benefits of an exercise and educational program in depression management have been identified for people with dementia.[156] Techniques such as affirmation, redirection, a calming environment, music, personalized care, and avoidance of physical restraint may mitigate resistant behavior in older people with dementia.[157]

Psychological interventions (e.g., cognitive behavioral therapy, interpersonal therapies) and music therapy may reduce symptoms of anxiety and depression in people with dementia.[141] [158]

Although evidence for efficacy of nonpharmacologic interventions for agitation and aggression in dementia is weak, these approaches tend to improve caregiver confidence and reduce caregiver distress.[159] [160]

Behavioral and psychological symptoms management: pharmacologic treatment

The goals of treatment should be to:

Reduce symptom severity

Improve the quality of life of the patient

Reduce caregiver stress.

Behavioral symptoms are common in people with AD: apathy (50%); agitation (50% to 70%); anxiety (30% to 50%); depression (25% to 50%); delusions (15% to 50%); sleep disorders (39%); hallucinations. (≤25%).[152] [161]

Cholinesterase inhibitors may be of modest benefit in the management of behavioral symptoms of dementia, but the evidence base is limited.[162] [163]

Depression

Very common in AD and significantly impacts on cognitive function as well as increasing caregiver stress. Clinical practice includes a trial of an antidepressant, particularly a selective serotonin-reuptake inhibitor (SSRI) (alongside consideration of nonpharmacologic interventions), and monitoring closely for efficacy, as it is not clear who will benefit.[164] Time-limited trials (i.e., 3-6 months) and careful monitoring of adverse effects and efficacy (e.g., using the Geriatric Depression Scale or the Cornell Scale for Depression in Dementia) are recommended.

SSRIs are considered the preferred treatment for depression in people with AD, although evidence suggests their clinical effectiveness may be very limited in these patients.[165] [166] [167] [168] Sertraline, citalopram, and escitalopram are preferred; SSRIs with a longer half-life (i.e., fluoxetine), those with increased potential for drug-drug interactions mediated by cytochrome P450 (fluoxetine, paroxetine, fluvoxamine), and those known to be more activating (e.g., paroxetine) should be used with caution.

Mirtazapine, an atypical antidepressant, is appropriate when poor appetite and insomnia are present.

Use of serotonin-norepinephrine reuptake inhibitors may be considered depending on patient preference, comorbidity, and clinician experience.

Tricyclic antidepressants should usually be avoided, as they require close monitoring by a caregiver because of the risk of lethal overdose and may have significant anticholinergic or cardiovascular adverse effects.

Insomnia

Low-dose trazodone or orexin antagonists may improve sleep in people with AD. [169]

Agitation and aggression

SSRIs reduce symptoms of agitation compared with placebo in people with dementia.[170] Data from one randomized controlled trial suggest that citalopram reduces agitation, irritability, anxiety, delusions, and caregiver distress.[171] [172] Those with milder cognitive impairment and moderate agitation were more likely to respond to citalopram.[173] Monitoring for cardiac side effects, such as prolonged QT interval, is important.

There is some evidence that carbamazepine is effective for the management of agitation and aggression in dementia.[174]

Trazodone may be considered when agitated behaviors associated with dementia are prevalent; it was associated with a lower rate of mortality than atypical antipsychotics, but a similar risk of falls and fractures, in older adults with dementia.[175] [176]

Dementia-related psychosis

Antipsychotic use in people with AD is controversial.[177] [178] The FDA has issued black box warnings for all atypical and typical antipsychotics in relation to dementia-related psychosis, as they have been shown to increase mortality. However, in cases of severe agitation or danger to self or others, antipsychotics have shown some benefit in management.

Risperidone, an atypical antipsychotic, may reduce behavioral symptoms of dementia.[179] [180]

All antipsychotics have the potential to cause extrapyramidal symptoms, but these adverse effects are less common with atypical antipsychotics than with conventional (typical) antipsychotics.[181] One systematic review and meta-analysis concluded that atypical antipsychotics (and cholinesterase inhibitors) may improve neuropsychiatric symptoms in patients with AD, but should be used with caution.[182]

If there is evidence of vascular dementia, antipsychotics should be used with extra caution and monitoring for cardiovascular adverse effects, because of the reported association with an increased incidence of stroke and cardiovascular events.

The American Psychiatric Association recommends reserving antipsychotics for symptoms that are considered severe, dangerous, and/or cause significant distress, and assessing efficacy and side effects to continuously balance the risk/benefit ratio in each individual patient.[183] Modifiable factors, such as pain, should be addressed prior to instituting therapy.

Low doses of antipsychotics may be prescribed cautiously in patients with neuropsychiatric symptoms. However:

All behavioral and psychosocial strategies should be exhausted first.[184]

Cognition and orientation should be monitored assiduously.

Risks should be discussed with caregivers and a decision made in collaboration with them.

Care should be used in institutional settings; dose increases can inadvertently occur, without adequate awareness of the risks, due to difficulties in managing challenging behaviors.

Treatment should be stopped if there is evidence of neurologic symptoms, increased confusion, or decline in mobility. In addition, monitoring for cardiac and metabolic side effects should be used appropriately.

Patients should be monitored for metabolic and cardiovascular side effects (e.g., ECGs, hemoglobin A1c).

Patients should be frequently assessed for efficacy of the intervention, and periodically for the need for ongoing treatment.[183]

Late-/end-stage care

Late-/end-stage care includes palliative measures, end-of-life choices, and discussing goals of care with the family. These issues are summarized in information on end-of-life planning from the Alzheimer’s Association. Alzheimer’s Association: end-of-life planning

It is important to review these issues in late-stage dementia, as overly aggressive care such as percutaneous endoscopic gastrostomy (PEG) feeding tubes can worsen morbidity and not improve quality of life or longevity.[185] Many patients do not want extreme measures if there is no possibility of independent function. Exploring family and patient preferences in the context of medical literature and information is enormously helpful.[186]

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