Alzheimer's disease

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

Treatment and care for people with AD should be individualised based on symptoms and social situation.[101][102][103][Evidence C]

Information and support

The first step following diagnosis is to provide education, support, and resources to the patient and the family.[104] 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 professional should be made available to provide emotional support and psychosocial input.

A referral should be made to a community service organisation, such as the Alzheimer's Association. Alzheimer's Association Opens in new window National Institute on Aging: about Alzheimer's disease - caregiving Opens in new window MedlinePlus: Alzheimer's caregivers Opens in new window Family Caregiver Alliance resource center Opens in new window Carer support groups have been shown to be beneficial to carers and should be considered, where available.[105]

The family should be aware that inevitable disease-related deficits will develop in memory, behaviour, 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 non-pharmacological and pharmacological treatments for the cognitive and behavioural 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 carers.

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.[104][106][107]

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.[108][109]

AD is a risk factor for falls and, therefore, fractures, especially in the context of certain medications for behaviour and changes in gait.[110][111] 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 pharmacological treatment goals are to:

Slow symptoms of disease progression by preserving memory and functional abilities
Reduce behavioural 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 pharmacological treatment are used:

Cholinesterase inhibitors[112]
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.[113][114]

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.[112] However, open-label extensions suggest that benefits may continue beyond 1 year with ongoing treatment.[115][116]

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.[117]

Cholinesterase inhibitors for mild to moderate AD

Oral rivastigmine and oral galantamine are approved by the US 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 rationalisation is an issue.[118]

Cholinesterase inhibitors for mild to severe AD

Oral donepezil and transdermal rivastigmine are FDA-approved for mild to severe AD.[119]

Donepezil has been shown to be beneficial at all stages of the disease.[120] Adverse effects, particularly gastrointestinal, are significantly more common with the higher-dose formulation approved for moderate to severe disease.[121] 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 carers to oral formulations.[122][123][124][125][126] [ ] Patients experiencing adverse effects with oral cholinesterase inhibitors may be transitioned to transdermal rivastigmine therapy without significant complications.[127]

Cholinesterase inhibitor efficacy

One randomised 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.[128] Patients who were assigned to discontinue donepezil and start memantine experienced similar benefits.[128] 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.

Pharmacological treatment with cholinesterase inhibitors was associated with reduced risk of death in one large, community-based observational study.[129] Retrospective data from the UK indicate that cholinesterase inhibitors are associated with a period of cognitive stabilisation (2 to 5 months) before a continued decline in cognitive function at the pre-treatment rate.[130]

Cognitive impairment: NMDA receptor antagonists

Memantine is indicated in moderate to severe AD, and is widely used off-label for mild AD.[131]

Memantine should be given as a sole treatment if cholinesterase inhibitors are contraindicated, are not tolerated, or have been shown to be ineffective.[132]

Co-administration of memantine with a cholinesterase inhibitor may be considered as the range of AD symptoms increases and the severity of behavioural 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.[131][133][134] [ ] [Evidence A] Meta-analyses suggest adding memantine to a cholinesterase inhibitor may modestly improve cognition in people with moderate to severe AD.[131][135][136]

Cognitive impairment: non-pharmacological treatments with limited evidence or no effectiveness

Exercise: meta-analyses suggest that exercise may improve cognition, with aerobic exercise being associated with greatest benefit.[137][138] An earlier Cochrane review found that exercise did not benefit cognition, but may improve activities of daily living in patients with dementia.[139]

Cognitive stimulation therapy/cognitive training: may improve cognitive function among patients with mild to moderate dementia, but evidence is of low quality.[51][Evidence C]What are the effects of cognitive training compared with usual care or no intervention for reducing the risk of cognitive decline and/or dementia in older adults with mild cognitive impairment?[51][137][140][141][142][143]

Occupational therapy: occupation-based interventions, physical exercise, and error-reduction techniques may delay functional decline in people with AD.[144]

Memory aids: may enhance verbal communication between individuals with AD and their carers.[145]

Music therapy: reported to moderately improve symptoms of depression, and possibly behaviour, emotional wellbeing, and anxiety, in patients with dementia, but with little or no effect on cognition, agitation, or aggression.[146] [ ] [Evidence B] 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.[147][148]

Validation therapy: insufficient evidence to recommend this intervention.[149] Validation therapy reinforces the reality and personal truth of the affected person.

Cognitive impairment: pharmacological treatments with limited evidence or no effectiveness

Non-steroidal 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.[150] [ ] 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.[151][152] [ ] [Evidence B]

Ginkgo biloba: evidence is inconsistent at best.[153][154] Ginkgo biloba is not routinely recommended because preparations (which are available without prescription) may differ with respect to purity, and concentration of active ingredient.

Behavioural and psychological symptoms of AD

Behavioural symptoms are intrinsic to AD and may become increasingly challenging to manage as the illness progresses. Behavioural 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 carer, the family, the physician, and the facility providing care for the patient. Behavioural strategies should be exhausted before considering pharmacological strategies. It is important to note that behavioural symptoms are associated with rapid progression[155] and are predictive of non-psychiatric admissions in this population, although the mechanism of this correlation is unknown.[156]

Behavioural and psychological symptoms management: non-pharmacological strategies

Families and carers 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 carers. Tagging with devices with global positioning technology has also been proposed and may offer some reassurance to carers about the patient’s safety. Alzheimer's Society: assistive technology 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 have been shown to improve sleep quality.[157][158]

Providing a well-structured, calm daily routine helps to modulate behaviours 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 that the environment is safe and removing unnecessary furniture and items that might harm patients if they wander.

Carer support and oral counselling should be provided, as this may help to delay entry to institutional care settings and reduces depression in the carer.[159][160]

Some functional benefits of an exercise and educational programme in depression management have been identified for people with dementia.[161] Techniques such as affirmation, redirection, a calming environment, music, personalised care, and avoidance of physical restraint may mitigate resistant behaviour in older people with dementia.[162]

Psychological interventions (e.g., cognitive behavioural therapy, interpersonal therapies) and music therapy may reduce symptoms of anxiety and depression in people with dementia.[146][163] [ ] [Evidence B]

Although evidence for efficacy of non-pharmacological interventions for agitation and aggression in dementia is weak, these approaches tend to improve carer confidence and reduce carer distress.[164][165]

Behavioural and psychological symptoms management: pharmacological treatment

The goals of treatment should be to:

Reduce symptom severity
Improve the quality of life of the patient
Reduce carer stress.

Behavioural 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%).[157][166]

Cholinesterase inhibitors may be of modest benefit in the management of behavioural symptoms of dementia, but the evidence base is limited.[167][168]

Depression

Very common in AD and significantly impacts on cognitive function as well as increasing carer stress. Clinical practice includes a trial of an antidepressant, particularly a selective serotonin-reuptake inhibitor (SSRI) (alongside consideration of non-pharmacological interventions), and monitoring closely for efficacy, as it is not clear who will benefit.[169] 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.[170][171][172][173] [ ] [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-noradrenaline 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 carer 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.[174]

Agitation and aggression

SSRIs reduce symptoms of agitation compared with placebo in people with dementia.[175] Data from one randomised controlled trial suggest that citalopram reduces agitation, irritability, anxiety, delusions, and also carer distress.[176][177] Those with milder cognitive impairment and moderate agitation were more likely to respond to citalopram.[178] 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.[179]

Trazodone may be considered when agitated behaviours 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.[180][181]

Dementia-related psychosis

Antipsychotic use in people with AD is controversial.[182][183] [ ] 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 behavioural symptoms of dementia.[184][185]

All antipsychotics have the potential to cause extrapyramidal symptoms, but these adverse effects are less common with atypical antipsychotics than with conventional (typical) antipsychotics.[186] 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.[187][Evidence A]What are the effects of pharmacological treatment on neuropsychiatric symptoms in people with Alzheimer's dementia?[187]

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.[188] 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 behavioural and psychosocial strategies should be exhausted first.[189]
Cognition and orientation should be monitored assiduously.
Risks should be discussed with carers 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 behaviours.
Treatment should be stopped if there is evidence of neurological 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, haemoglobin A1c).
Patients should be frequently assessed for efficacy of the intervention, and periodically for the need for ongoing treatment.[188]

Late-/end-stage care

Late-/end-stage care includes palliative measures, end-of-life choices, and discussing goals of care with the family.[104][106] These issues are summarised 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.[190] 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.[102]

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