7.5.1 Alzheimer's disease

Definition and classification

Alzheimer's disease is defined by amyloid beta plaques and tau neurofibrillary tangles. It usually presents as gradual loss of episodic memory followed by wider cognitive and functional decline, though non-amnestic presentations occur.

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• ICD-11 dementia requires cognitive decline that interferes with independence; mild neurocognitive disorder leaves independence largely intact.

Pathology and neurochemistry

• The amyloid cascade hypothesis holds that abnormal amyloid processing and aggregation lead on to tau change, synaptic dysfunction, inflammation and neuronal loss. Familial genetics support it, but it does not explain individual onset or severity.

• Tau distribution and synaptic loss track cognitive severity more closely than amyloid burden does, and some cognitively normal older adults carry heavy amyloid.

• Tangle pathology begins in the entorhinal cortex and hippocampus, so recent memory fails first and medial temporal atrophy appears first on imaging.

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• Cholinergic loss is the rationale for cholinesterase inhibitors, but it does not explain the whole disease.

Genetics

Genes and chromosomes

• Rare pathogenic variants in APP, PSEN1 or PSEN2 cause familial young-onset disease and warrant genetic counselling.

Apolipoprotein E

• APOE ε4 is a susceptibility factor, neither necessary nor deterministic. One copy roughly triples the risk of late-onset disease and two copies raise it much further, yet neither makes the disease certain.

• More than half of people with late-onset Alzheimer's disease carry at least one ε4 allele, against about a quarter of the population.

• APOE ε2 without ε4 is protective, graded as proven, and carriers deposit less amyloid than ε3 homozygotes.

• APOE testing for anti-amyloid treatment safety differs from testing for rare causative variants, and APOE is not a diagnostic test.

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Down syndrome

• Down syndrome is a proven risk factor because the extra chromosome 21 gives a third copy of the APP gene.

• Pathology is near-universal by 40, lifetime risk exceeds 90% and dementia often begins in the fifties.

• Atrophy mirrors the sporadic pattern: posterior-predominant cortical thinning with hippocampal, thalamic and striatal atrophy.

Epidemiology and risk factors

• Age is the strongest common risk factor: incidence and prevalence roughly double with each five years after 65, so they rise about sixteenfold over 20 years.

• Alzheimer's disease, alone or mixed with vascular pathology, accounts for about 60 to 70% of dementia.

• A 2024 UK estimate put all-cause dementia near 982,000 people, with about 1.4 million projected by 2040.

• Higher prevalence in women partly reflects their longer survival.

• One first-degree relative with late-onset disease raises risk three- to fourfold, so a baseline of about 5% becomes roughly 15 to 20% by age 85.

• Smoking once looked protective because survival bias distorted case-control samples, but prospective cohorts show it is a risk factor.

Clinical features and course

Cognitive and functional decline

• Recent memory loss is the earliest characteristic feature: people struggle to learn and recall new information, repeat questions and forget recent conversations.

• Remote memories and familiar skills are relatively preserved early on.

• Difficulty with money, medication and unfamiliar tasks comes before dependence in basic self-care.

• Language, visuospatial, praxis and executive deficits follow as the disease spreads.

• Late features include gait disorder, loss of mobility, urinary incontinence, seizures and dysphagia.

Atypical presentations

Both often reflect Alzheimer pathology but need differential assessment.

Neuropsychiatric symptoms

• Behavioural and psychological symptoms of dementia are separate from the cognitive deficits and fall into two groups: behavioural (observed acts such as wandering, hoarding, aggression, disinhibition) and psychological (anxiety, low mood, delusions, hallucinations, misidentification).

• Apathy is the commonest, ahead of depression, aggression and anxiety.

• Depression becomes commoner from mild to moderate dementia and is recorded less often in severe dementia, whereas cognitive, language, functional and extrapyramidal measures worsen steadily.

• Delusions, usually persecutory, occur in about twice as many patients as hallucinations, and Schneiderian first-rank symptoms are rare.

Prognosis

• Survival after diagnosis is often quoted as four to eight years but varies widely, with no fixed time to complete dependence.

• Later age at onset predicts slower decline, whereas other baseline clinical and biomarker features predict faster decline.

• Pneumonia, usually from aspiration due to dysphagia and immobility, is the commonest cause of death.

Mild cognitive impairment

• Mild cognitive impairment affects cognition without the loss of independence that dementia requires. It has several causes, so it does not establish Alzheimer pathology.

• About 10% of people with amnestic mild cognitive impairment progress to Alzheimer's dementia each year (10 to 15% in clinic cohorts), above the background incidence in healthy older adults.

• Only about 30 to 40% have dementia after ten years, so most do not progress.

• No drug or supplement is recommended to prevent conversion to dementia, and cholinesterase inhibitors and memantine are not routine treatment.

• Regular exercise is the only intervention with reasonable evidence of improving cognition in mild cognitive impairment.

Differential diagnosis

• Normal pressure hydrocephalus is a reversible mimic with gait disturbance, urinary incontinence and cognitive decline, ventricular enlargement on imaging and a normal cerebrospinal fluid (CSF) opening pressure.

• Gait disorder and incontinence early in the illness argue against Alzheimer's disease, where they come late, and towards normal pressure hydrocephalus.

• Delirium, depression, sensory impairment and medicines are checked as treatable contributors, and normal ageing never explains progressive loss of independence.

Diagnosis and investigation

Clinical criteria

• The 2011 NIA-AA criteria (National Institute on Aging and Alzheimer's Association) for probable Alzheimer's dementia require insidious onset, clear worsening and an amnestic or non-amnestic leading deficit.

• They exclude acute onset, significant cerebrovascular disease, core Lewy body features, prominent behavioural-variant frontotemporal dementia features and non-logopenic primary progressive aphasia features.

• Under these criteria biomarkers can add certainty but are not advocated for routine use, because standardisation and access are limited.

• Poor delayed recall with little benefit from cueing supports an amnestic storage deficit but does not alone establish the disease.

Staging

The National Institute for Health and Care Excellence (NICE) stages severity by Mini-Mental State Examination (MMSE) score.

Tests

• First-line tests are bloods for treatable contributors, and NICE advises against electroencephalography (EEG) in the routine work-up.

• Structural imaging excludes other causes. Medial temporal (hippocampal) atrophy is the earliest characteristic change on magnetic resonance imaging (MRI), but it is neither necessary nor sufficient.

• NICE NG97 advises fluorodeoxyglucose positron emission tomography (FDG-PET), which maps glucose metabolism, when Alzheimer's disease is suspected but uncertain; dopaminergic and cardiac sympathetic scans belong to the Lewy body pathway.

• CSF amyloid and tau testing is a specialist option when subtype remains uncertain and the result would change care.

• Blood biomarkers such as phosphorylated tau belong only in a validated, governed pathway and are read alongside the clinical assessment.

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Cholinesterase inhibitors

• Donepezil, rivastigmine and galantamine are symptomatic treatments for mild to moderate Alzheimer's disease, chosen by cost, tolerability, comorbidity and interactions.

• They are not stopped only because dementia becomes severe; benefit, adverse effects and goals are reviewed instead.

• Tacrine, the first approved, was withdrawn for hepatotoxicity (raised transaminases) and needed dosing four times daily.

The three drugs

Rivastigmine formulations

• Capsules and oral solution are also UK-licensed for mild to moderate dementia in Parkinson's disease, whereas the patch is licensed for Alzheimer's disease only.

• The patch starts at 4.6 mg/24 hours, rises to 9.5 mg/24 hours after at least four weeks, and may reach 13.3 mg/24 hours after six months at 9.5 mg in a tolerant patient with meaningful decline.

• Switching to the patch avoids the peak plasma levels that cause nausea and vomiting, and keeps a response that is already working.

Adverse effects

Memantine

• Memantine is an uncompetitive, voltage-dependent N-methyl-D-aspartate (NMDA) receptor channel blocker that damps tonic glutamate excitotoxicity while sparing normal transmission.

• It starts at 5 mg once daily and rises by 5 mg each week to 20 mg once daily; older UK practice gave 10 mg twice daily.

• It is renally eliminated, so very severe renal impairment (estimated glomerular filtration rate below 5 mL/minute) rules it out.

• NICE recommends memantine alone for moderate Alzheimer's disease when cholinesterase inhibitors are contraindicated or not tolerated, such as sick sinus syndrome with syncope, and for severe disease.

• In someone already taking an inhibitor, memantine is considered as an add-on in moderate disease and offered in severe disease.

Drug choice by dementia type

Anti-amyloid antibodies

• Lecanemab and donanemab reduce amyloid and modestly slow decline in selected early disease (mild cognitive impairment or mild dementia with confirmed amyloid), but they do not restore function or cure.

• Lecanemab is an intravenous monoclonal antibody given every two weeks.

• The Medicines and Healthcare products Regulatory Agency licensed lecanemab in August 2024 and donanemab in October 2024 for people with one or no APOE ε4 copies.

• APOE ε4 homozygotes carry the highest risk of adverse effects and are excluded from the UK licence.

• Treatment needs confirmed amyloid, genotyping, assessment of contraindications and bleeding risk, infusion services, and MRI before and during treatment.

• Amyloid-related imaging abnormalities (ARIA) are oedema or effusion (ARIA-E) and microhaemorrhage or superficial siderosis (ARIA-H). Most are silent on imaging, but severe and fatal cases occur.

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• Lecanemab's 27% relative slowing on the Clinical Dementia Rating sum of boxes over 18 months was an absolute difference under half a point on an 18-point scale.

• NICE has not recommended NHS use on cost-effectiveness grounds and its appraisals remain in draft; licensing and NHS funding are separate decisions.

Other treatment and support

• Ginkgo biloba has inconsistent trial evidence, is not recommended by NICE for dementia and adds to bleeding risk.

• Cognitive stimulation, meaningful activity, occupational therapy and cognitive rehabilitation help chosen goals, but gains in symptoms or quality of life do not mean slower pathology.

• Carers are offered education, support and respite, and their own health and ability to keep caring are assessed.

Behavioural and psychological symptoms

Assessment and non-drug care

• Pain, constipation, infection, delirium, medication effects, communication, unmet needs and the care environment are assessed before prescribing for agitation or psychosis.

• Untreated pain is treated first, and regular paracetamol has trial evidence for reducing agitation in care home residents with dementia.

• Music-based therapy has the strongest trial evidence among non-drug interventions, chiefly for mood and overall behaviour; aromatherapy, light therapy, multisensory rooms and massage are unproven.

Drugs

• Risperidone is the only antipsychotic UK-licensed for short-term treatment (up to six weeks) of persistent aggression in moderate to severe Alzheimer's dementia, once non-drug measures fail and others are at risk.

• It is used at low dose with a recorded discussion of stroke and mortality risk; the licensed ceiling is 1 mg twice daily (2 mg in 24 hours), though most patients need about 500 micrograms twice daily.

• Any antipsychotic is given at the lowest effective dose, briefly, and reviewed early and at least every six weeks; severe sensitivity in Lewy body disease remains a danger.

• After an acute cerebral infarct, psychotropic drugs are avoided where possible and agitation is managed without them.

• Psychosis in Parkinson's disease is treated by first reducing provoking dopaminergic drugs, then quetiapine, then low-dose clozapine, which is UK-licensed for this use with blood monitoring.

Advanced disease and planning

• The diagnosis is explained in manageable stages with the person's chosen supporters, and revisited as needs change.

• Advanced disease brings aspiration, infection, pressure injury and malnutrition; it is life-limiting, so palliative care runs alongside other treatment.

• Artificial feeding is not routinely beneficial in severe dementia, although a potentially reversible problem may change the decision.

• Advance statements, treatment refusals and powers of attorney are planned while capacity remains, and capacity is assessed for each decision.

• Dementia must be notified to the Driver and Vehicle Licensing Agency or Driver and Vehicle Agency, but some people with mild disease keep driving under review; mild cognitive impairment has different criteria.