Key Facts

AD is a progressive neurodegenerative disease with no cure. Current treatments provide modest symptomatic benefit. Diagnosis is clinical, supported by biomarkers. Research into disease-modifying therapies (anti-amyloid antibodies) is advancing rapidly.

Epidemiology

Prevalence: ~1% at 65, doubling every 5 years (~30-40% at 85). F > M (~2:1, partly due to longer life expectancy). Early-onset AD (<65 years) accounts for ~5% and is more likely to be familial/genetic.

Aetiology

• Sporadic (~95%): multifactorial - age, genetics (APOE ε4), cardiovascular risk factors, lifestyle
• Familial/autosomal dominant (~5% of early-onset): APP (chromosome 21), PSEN1 (chromosome 14 - commonest familial), PSEN2 (chromosome 1); autosomal dominant with near-complete penetrance

Pathophysiology

Early Stage

• Episodic memory loss: forgetting recent events, repetitive questioning; remote memory preserved
• Word-finding difficulty: circumlocution, reduced vocabulary
• Spatial disorientation: getting lost in familiar places
• Executive dysfunction: difficulty managing finances, medication, planning

Moderate Stage

• Progressive memory loss (affecting remote memory)
• Language decline (reduced fluency, comprehension difficulties)
• Apraxia (difficulty with learned motor tasks - dressing, using utensils)
• Agnosia (failure to recognise objects/people)
• Behavioural changes: apathy (commonest), depression, agitation, wandering
• Sundowning: worsening confusion/agitation in late afternoon/evening

Severe Stage

• Profound memory loss, minimal speech, loss of recognition
• Dependence for all ADLs
• Incontinence, dysphagia, immobility
• Death usually from pneumonia/infection

Atypical Variants

• Posterior cortical atrophy (PCA): visual/spatial processing difficulties; younger onset
• Logopenic progressive aphasia: word-finding difficulty, sentence repetition impairment
• Frontal variant: executive dysfunction, behavioural features (mimics FTD)

Red Flags

• Rapid progression (weeks-months) → NOT typical AD; consider CJD, autoimmune
• Early prominent hallucinations → DLB rather than AD
• Early personality/behavioural change → FTD
• Age <65 → consider familial AD, genetic testing

Cognitive Testing

• ACE-III (≤88/100), MoCA (≤25/30), MMSE (≤24/30)
• Formal neuropsychological assessment for atypical/young-onset cases

Imaging

• MRI brain: medial temporal lobe/hippocampal atrophy (Scheltens visual scale); parietal atrophy; global atrophy in later stages
• FDG-PET: temporal-parietal hypometabolism (characteristic of AD)
• Amyloid PET: detects amyloid plaques in vivo; used in specialist/research settings; high sensitivity

CSF Biomarkers

• Aβ42: LOW in AD (amyloid sequestered in plaques)
• Total tau and phospho-tau (p-tau): HIGH in AD
• Aβ42/Aβ40 ratio: more accurate than Aβ42 alone
• Increasingly used in clinical practice for diagnostic certainty

Bloods

• Exclude reversible causes: FBC, U&Es, calcium, TFTs, B12/folate, LFTs, glucose
• Blood-based biomarkers (p-tau217, Aβ42/40): emerging; may transform diagnosis in future

Genetic Testing

• APOE genotyping: risk factor (not diagnostic); not routinely recommended in clinical practice
• APP, PSEN1, PSEN2: for familial early-onset AD; genetic counselling essential

Pharmacological (NICE TA217)

Mild-Moderate AD:

• Cholinesterase inhibitors (ChEIs): first-line
  • Donepezil 5mg OD → 10mg OD after 4-6 weeks (commonest prescribed)
  • Rivastigmine patches 4.6-13.3mg/24h or oral 1.5-6mg BD (also licensed for PDD)
  • Galantamine 8-24mg OD (MR)
• Side effects: nausea, diarrhoea, insomnia, vivid dreams, bradycardia, syncope
• Monitor: pulse, weight; ECG if cardiac history

Moderate-Severe AD:

• Memantine 10-20mg OD: NMDA receptor antagonist; used alone or with ChEI
• Side effects: dizziness, headache, constipation

Combination: donepezil + memantine commonly used in moderate-severe AD

Non-Pharmacological

• Cognitive stimulation therapy (CST): NICE-recommended; group activities 2×/week
• Exercise: evidence for slowing cognitive decline
• Social engagement, meaningful activities
• Music therapy, reminiscence therapy

BPSD Management

• Non-pharmacological first: identify triggers, person-centred approach
• Risperidone: only licensed antipsychotic for short-term aggression in AD (max 6 weeks; NICE)
• Avoid antipsychotics if possible (increased stroke/death risk in dementia)

Carer Support

• Alzheimer's Society referral
• Carer assessment (local authority)
• Respite care
• Financial support: attendance allowance, lasting power of attorney

Advance Care Planning

• Lasting power of attorney (while capacity retained)
• Advance decisions to refuse treatment (ADRT)
• Preferred place of care/death

Referral Criteria

• Memory assessment service: all suspected AD
• Young-onset (<65): specialist service, genetics
• Complex BPSD: old age psychiatry

Progressive and invariably fatal. Mean survival from diagnosis ~8-10 years (range 3-20 years). Younger onset: faster progression. Death usually from pneumonia, other infections, or cardiovascular disease. ChEIs and memantine provide modest symptomatic benefit (equivalent to ~6-12 months delay in decline) but do not alter disease course. Anti-amyloid immunotherapies (lecanemab, donanemab) show modest slowing of decline in trials but with significant side effects (ARIA - amyloid-related imaging abnormalities).

AD Risk Genes

Braak Staging (Neurofibrillary Tangles)