Alzheimer disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Your Organizational Guidance

ebpracticenet urges you to prioritize the following organizational guidance:

Guide de pratique clinique pluridisciplinaire relatif à la collaboration dans la dispense de soins aux personnes âgées démentes résidant à domicile et leurs aidants prochesPublished by: Groupe de Travail Développement de recommmandations de première ligneLast published: 2017Multidisciplinaire richtlijn voor thuiswonende oudere personen met dementie en hun mantelzorgersPublished by: Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2017

Treatment and care for people with Alzheimer disease (AD) should be individualized based on symptoms and social situation, and involve a multidisciplinary team.[152] The COVID-19 pandemic has demonstrated that telemedicine can be employed for dementia evaluation and support and this may be a way to reduce patient and caregiver burden.[153]

Information and support

The first step following diagnosis is to provide education, support, and resources to the patient and the family.[154] This news is often devastating and may provoke many questions about the disease process, time course, and potential treatment options. A social worker, psychologist, or other mental health professional 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 Opens in new window Alzheimer's and related Dementias Education and Referral (ADEAR) Center Opens in new window National Institute on Aging: Alzheimer's caregiving Opens in new window MedlinePlus: Alzheimer's caregivers Opens in new window Family Caregiver Alliance resource center Opens in new window Caregiver support groups have been shown to be beneficial to caregivers and should be considered, where available.[155]

The family should be aware that inevitable disease-related deficits will develop in memory, behavior, mood, and function (ranging from functional risks such as financial risks and driving risks, to late-stage physical risks such as incontinence, immobility, and 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.

Discussion of advanced directives and end-of-life care that may be anticipated should take place at an early stage, and needs to be handled sensitively, based on a good patient-provider and family-provider relationship.[154][156][157]

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.[158][159]

AD is a risk factor for falls and, therefore, fractures, especially in the context of certain drugs for behavior and changes in gait.[160][161] Therefore, an assessment of the risk of falls, and interventions to mitigate the risk, should be incorporated in the home safety evaluation.[162] National Institute on Aging: Alzheimer's caregiving - home safety tips Opens in new window

Goals of pharmacotherapy

The major pharmacologic 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 to address the cognitive symptoms of dementia are used:[163][164][165]

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. A cholinesterase inhibitor may be combined with the NMDA receptor antagonist memantine for potentially greater benefits.[165][166][167]

Cholinesterase inhibitors and memantine 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.[168] One Cochrane review concluded that discontinuing cholinesterase inhibitors may result in worse cognitive, neuropsychiatric, and functional status than if treatment is continued, but the evidence was limited, and it is unclear whether there are differences based on severity of dementia. No evidence was found to guide decisions about discontinuing memantine.[169] An individualized approach is recommended, taking into account the wishes of patients and caregivers.[168][169]

The new monoclonal antibodies aim to be disease-modifying. However, the potential and magnitude of this effect is still being explored.

Pharmacotherapy: 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.

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 may improve compliance.[170]

There are some data to suggest that switching between cholinesterase inhibitors may enhance efficacy and/or improve tolerability.[171]

Oral and transdermal donepezil and transdermal rivastigmine are FDA-approved for mild to severe AD.[172] The rivastigmine transdermal patch may increase compliance and reduce cholinergic adverse effects, and is preferred by caregivers to the oral formulation.[173][174] [ ] Patients experiencing adverse effects with oral cholinesterase inhibitors may be transitioned to transdermal rivastigmine therapy without significant complications.[175]

The clinical benefit of cholinesterase inhibitors is modest.[163][164] Pharmacologic treatment with cholinesterase inhibitors was associated with reduced risk of death in one large, community-based observational study.[176] Retrospective data from the UK indicate that cholinesterase inhibitors are associated with a period of cognitive stabilization (2-5 months) before a continued decline in cognitive function at the pretreatment rate.[177]

Donepezil has been shown to be beneficial at all stages of the disease.[178] Adverse effects, particularly gastrointestinal, are significantly more common with the higher-dose formulation approved for moderate to severe disease.[179] Increasing the dose to the high end of the dose range may confer only modest benefit.

Pharmacotherapy: NMDA receptor antagonists

Memantine is indicated in moderate to severe AD, and is widely used off-label for mild AD.[165]

Memantine should be given as a sole treatment if cholinesterase inhibitors are contraindicated, are not tolerated, or have been shown to be ineffective.[165]

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.[165]

Memantine is well tolerated, and modestly improves outcomes compared with placebo in moderate to severe AD, but evidence suggests no benefit in mild AD.[165] [ ] [Evidence A] Meta-analyses suggest adding memantine to a cholinesterase inhibitor may modestly improve cognition in people with moderate to severe AD.[165][180]

Nonpharmacologic treatments

Exercise and physical activity: meta-analyses suggest that exercise may improve cognition, with aerobic exercise being associated with greatest benefit.[181][182] An earlier Cochrane review found that exercise did not benefit cognition, but may improve activities of daily living in patients with dementia.[183]

Cognition-focused interventions: cognitive stimulation therapy, cognitive training, and cognitive rehabilitation may improve cognitive function among patients with mild to moderate dementia, but evidence is of low quality.[73][181][184][185][186][187][188][189][Evidence C]

Occupational therapy: occupation-based interventions, physical exercise, and error-reduction techniques may delay functional decline in people with AD.[190]

Memory aids: may enhance verbal communication between individuals with AD and their caregivers.[191]

Music therapy: one systematic review found high-quality evidence that music therapy improves cognition in AD patients, with a greater effect when patients are involved in the music making themselves.[192] 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.[193] 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.[194][195]

Validation therapy: reinforces the reality and personal truth of the affected person. Although there is little objective evidence, a few recent studies have demonstrated that components of validation therapy elicit better patient responses in a secondary analysis.[196][197] A nursing home in which these principles were implemented demonstrated better staff satisfaction and decreased need for drug treatment for agitation.[198]

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.[199] [ ] 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.[200][201] [ ] [Evidence B]

Ginkgo biloba: evidence is inconsistent at best.[167][202][203][204] 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, becoming increasingly challenging to manage as the illness progresses, and are predictive of nonpsychiatric admissions in this population.[205][206] Behavioral and psychological symptoms of AD include: apathy (45% to 60% of patients); agitation (50% to 70%); anxiety (30% to 50%); depression (25% to 50%); delusions (15% to 50%); sleep disorders (39%); hallucinations (≤25%); and psychosis.[207][208][209]

The goals of treatment should be to:

Reduce symptom severity
Improve the quality of life of the patient
Reduce caregiver stress

Management 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.

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 has also been proposed and may offer some reassurance to caregivers about the patient’s safety.[210] Alzheimer's Society: how technology can help Opens in new window

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 may improve sleep quality, and improve behavioral symptoms.[211][212][213][214]

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 night time
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.[215][216]

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.[217]

Psychological interventions (e.g., cognitive behavioral therapy, interpersonal therapies) and music therapy may reduce symptoms of anxiety and depression in people with dementia.[193][218][219] [ ] [Evidence B] One systematic review concluded that nondrug interventions (e.g., cognitive stimulation, massage and touch therapy, exercise, reminiscence therapy) were more effective than drug interventions for reducing symptoms of depression in people with dementia without a major depressive disorder.[220]

Evidence for efficacy of nonpharmacologic interventions for agitation and aggression in dementia is relatively weak, but network meta-analyses have suggested that massage therapy, animal-assisted intervention, multidisciplinary care, and personally tailored intervention are associated with reductions in agitation compared with other interventions and controls. These approaches also tend to improve caregiver confidence and reduce caregiver distress.[221][222][223][224]

Behavioral and psychological symptoms management: pharmacologic treatment

Management of behavioral and psychological symptoms can be complex and treatment should be individualized.[225][226]

Cholinesterase inhibitors may be of modest benefit in the management of behavioral symptoms of dementia, including psychotic symptoms, but the evidence base is limited.[227][228][229]

Depression

Depression is very common in patients living with 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; see above), and monitoring closely for efficacy, as it is not clear who will benefit.[230] 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.[231][232][233][234][235] [ ] [Evidence A]

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 (SNRIs) 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, orexin receptor antagonists, or melatonin may improve sleep in people with AD, but evidence is scarce.[213][236][237]

Agitation and aggression

SSRIs reduce symptoms of agitation compared with placebo in people with dementia.[238] Data from one randomized controlled trial suggest that citalopram reduces agitation, irritability, anxiety, delusions, and also caregiver distress.[239][240] Those with milder cognitive impairment and moderate agitation were more likely to respond to citalopram.[241] 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.[242]

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.[243][244]

Dementia-related psychosis

Antipsychotic use in people with AD is controversial.[208][245] [ ] The FDA has issued 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.[208][245]

Brexpiprazole is effective for the treatment of agitation in patients with AD and is better tolerated and safer compared with currently available second-generation antipsychotics.[246][247][248]

All antipsychotics have the potential to cause extrapyramidal symptoms, but these adverse effects are less common with atypical antipsychotics than with conventional (typical) antipsychotics.[208][249]

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.[250][Evidence A]What are the effects of pharmacologic treatment on neuropsychiatric symptoms in people with Alzheimer dementia?[250] Atypical antipsychotics that may reduce behavioral symptoms of dementia include risperidone, olanzapine, aripiprazole, and quetiapine, but one Cochrane review concluded that the effects of atypical antipsychotics on psychosis in dementia is negligible.[208][251]

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.[252]

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.[253] 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.[254]
Cognition and orientation should be monitored assiduously.
Risks should be discussed with caregivers and a decision made in collaboration with them.
Particular 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.[253]

Late-/end-stage care

Late-/end-stage care includes palliative measures, end-of-life choices, and discussing goals of care with the family.[154][156] These issues are summarized in information on end-of-life planning from the Alzheimer's Association. Alzheimer's Association: end-of-life planning Opens in new window 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.[255] 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.[256]

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