Alzheimer disease

At a glance

• The commonest cause of dementia, about 60 to 70% of cases, often mixed with vascular and Lewy body pathology in people over 80.
• Typical picture: insidious episodic memory loss with poor insight, then language, visuospatial, executive and behavioural decline over 8 to 10 years.
• Pathology begins 15 to 20 years before symptoms. The 2024 Alzheimer's Association criteria define the disease biologically by amyloid biomarkers.
• Cholinesterase inhibitors and memantine give small symptomatic gains. Anti-amyloid antibodies modestly slow early disease, with ARIA as the main risk.
• Most of the work is diagnosis disclosure, planning, carer support and safety.
• The comparison with vascular, Lewy body and frontotemporal dementia, and driving rules, are in Dementia syndromes. The approach to a memory complaint is in Approach to memory disturbance.

Definitions and staging

Stage	Features
Preclinical	Amyloid positive, cognitively normal. Not a clinical diagnosis outside research
MCI due to Alzheimer disease	Objective decline, usually amnestic; independent in daily activities
Mild dementia	Loses complex tasks: finances, medicines, driving, cooking
Moderate dementia	Needs help with dressing and hygiene; BPSD common; wandering
Severe dementia	Dependent for all care, limited speech, incontinence, dysphagia, immobility

• Alzheimer's Association revised criteria (Jack 2024): Alzheimer disease is diagnosed by an abnormal core 1 biomarker (amyloid PET, CSF amyloid beta 42/40 ratio or p-tau/amyloid ratio, or an accurate plasma p-tau217 assay), whatever the symptoms. Tau PET and other markers stage it.
• International Working Group (Dubois 2024) objects to labelling asymptomatic amyloid-positive people. For them it is a "risk state", and Alzheimer disease means a typical clinical phenotype plus biomarkers.
• In practice and in exams, diagnosis is clinical, with biomarkers to confirm in atypical, young-onset or treatment-eligible patients.

Causes and risk factors

• Age is the dominant risk. Prevalence roughly doubles every 5 years after 65.
• APOE e4 (chromosome 19): one copy about triples risk, two copies raise it about 10 to 12 times. APOE e2 is protective. Don't test APOE to diagnose; test it before anti-amyloid therapy, after counselling.
• Autosomal dominant disease (under 1% of cases, onset often in the 40s and 50s): PSEN1 (commonest), APP and PSEN2.
• Down syndrome: three copies of APP on chromosome 21. Most have Alzheimer pathology by 40 and dementia is common by the late 50s. See Down syndrome.
• Modifiable (Lancet Commission 2024): 14 factors account for about 45% of dementia, including hearing loss, high LDL cholesterol, hypertension, diabetes, smoking, physical inactivity, depression, social isolation, untreated vision loss, low education and excess alcohol.
• Aboriginal and Torres Strait Islander people have dementia rates about 3 to 5 times higher, with earlier onset.

Pathophysiology

• Amyloid cascade: APP is cleaved by beta- and gamma-secretase (presenilin is part of gamma-secretase) into amyloid beta 42, which aggregates into oligomers and plaques.
• Tau: hyperphosphorylated tau forms neurofibrillary tangles, spreading from the entorhinal cortex and hippocampus to the neocortex (Braak stages). Tangles, synapse loss and atrophy correlate with symptoms better than plaques.
• Cholinergic deficit: loss of neurons in the nucleus basalis of Meynert reduces cortical acetylcholine, the basis for cholinesterase inhibitors.
• Glutamate excitotoxicity through NMDA receptors is the rationale for memantine.
• Cerebral amyloid angiopathy coexists in most patients. It causes lobar haemorrhage and microbleeds, and underlies the bleeding risk of ARIA.

Recognition

Typical amnestic presentation

• Repeating questions and stories, misplacing things, missed appointments, forgetting recent conversations. Remote memory is preserved early.
• Brought by family, who notice more than the patient. Lack of insight (anosognosia) is common.
• Word-finding difficulty, getting lost in unfamiliar places, then familiar ones.
• Apathy and depression often precede the diagnosis.
• Examination: usually normal neurology early. Delayed recall poor and not improved by cueing. Head-turning sign (looking to the carer for answers).
• Parkinsonism, myoclonus and seizures appear late. Early parkinsonism or hallucinations suggest Lewy body disease.

Atypical variants

• Posterior cortical atrophy: visuospatial, reading and dressing difficulty with preserved memory; often seen first by an optometrist.
• Logopenic primary progressive aphasia: word-finding pauses and poor sentence repetition.
• Frontal (dysexecutive) variant: executive and behavioural change, easily mistaken for FTD.
• Atypical variants are more common in young-onset disease.

Pitfall: an MMSE in the normal range doesn't exclude early Alzheimer disease in a highly educated person. The MoCA is more sensitive, and formal neuropsychology settles doubt.

Investigations

• Reversible screen: FBC, UEC, calcium, glucose, LFTs, TSH, B12 and folate; syphilis and HIV serology where there is risk.
• Structural imaging for everyone: MRI preferred. Medial temporal (hippocampal) atrophy and parietal atrophy support Alzheimer disease; MRI also shows vascular burden, microbleeds and alternative causes.
• FDG-PET: temporoparietal and posterior cingulate hypometabolism.
• Amyloid confirmation (needed before anti-amyloid therapy, and useful in atypical or young-onset disease):

Test	Alzheimer pattern
CSF	Low amyloid beta 42 or low 42/40 ratio, high p-tau, high total tau
Amyloid PET	Diffuse cortical tracer uptake
Plasma p-tau217	Raised. High accuracy for amyloid pathology; a negative result makes Alzheimer pathology unlikely. Entering Australian practice; check local availability

• APOE genotyping before anti-amyloid therapy, because homozygotes are excluded.
• Genetic testing (PSEN1, APP, PSEN2) for young onset with a dominant family history, with genetic counselling and consent for predictive testing of relatives.

Management

Non-drug care

• Disclose the diagnosis clearly, with written information. Refer to Dementia Australia (National Dementia Helpline 1800 100 500).
• Legal planning while capacity remains: enduring power of attorney, enduring guardianship, advance care directive and will.
• Driving: no unconditional licence; see Dementia syndromes.
• My Aged Care assessment, carer education and respite.
• Cognitive stimulation therapy, exercise, treating hearing and vision loss, and managing vascular risk.
• Review medicines for anticholinergic and sedative load.

Cholinesterase inhibitors

• Donepezil, rivastigmine (capsule or patch) and galantamine are equally effective. Benefit is modest: a few points on cognitive scales and slower functional decline.
• Start low and titrate. Donepezil 5 mg at night for 4 to 6 weeks, then 10 mg; give it in the morning if dreams are vivid.
• Adverse effects: nausea, diarrhoea, weight loss, vivid dreams, muscle cramps, urinary urgency, and vagotonic bradycardia, heart block and syncope. Check pulse and ECG first.
• DOMINO-AD (Howard, NEJM 2012): in moderate to severe disease, stopping donepezil led to faster cognitive and functional decline. A secondary analysis (Lancet Neurol 2015) found more nursing home placement in the first year off donepezil, with no difference over 3 years. Adding memantine to donepezil gave no significant extra benefit. Don't stop a tolerated drug only because the person is still declining.
• PBS: Authority listings for Alzheimer disease confirmed by a specialist or in consultation with one, with a baseline MMSE or SMMSE, and evidence of response for continuation. Check the current wording.

Memantine

• NMDA antagonist for moderately severe disease (PBS Authority, MMSE 10 to 14). The PBS listing is for monotherapy: memantine added to a cholinesterase inhibitor isn't subsidised. NICE NG97 does suggest add-on memantine in moderate to severe disease, though DOMINO-AD showed no significant gain from the combination. Check the current PBS wording.
• Dizziness, headache, confusion. Halve the dose when creatinine clearance is under 30 mL/min.

Pitfall: new urinary urgency after starting donepezil, treated with oxybutynin. That is a prescribing cascade. See Urinary and faecal incontinence.

Anti-amyloid monoclonal antibodies

	Lecanemab	Donanemab
Trial	CLARITY AD (2023)	TRAILBLAZER-ALZ 2 (2023)
Population	MCI or mild dementia, amyloid positive	MCI or mild dementia, amyloid and tau positive
Benefit	27% slower decline on CDR-SB over 18 months (0.45 points)	About 35% slower decline in low to intermediate tau over 76 weeks
Dosing	10 mg/kg IV every 2 weeks, with MRI before the 3rd, 5th, 7th and 14th infusions; the Australian PI has no other regimen and asks for review of benefit at 18 months. Overseas labels allow 4-weekly IV maintenance after 18 months, and the US has a subcutaneous autoinjector (2025)	IV every 4 weeks, titrated; stop when amyloid clears (up to 18 months)
ARIA	ARIA-E about 13%	ARIA overall 37% versus 15% placebo; ARIA-E about 24%

• ARIA-E is vasogenic oedema or sulcal effusion; ARIA-H is microhaemorrhage or superficial siderosis. Most is asymptomatic and found on scheduled MRIs. Symptoms are headache, confusion, visual change and seizures; rarely it is fatal. Risk is highest in APOE e4 homozygotes.
• Symptomatic or moderate to severe ARIA: suspend dosing, repeat MRI, and give high-dose corticosteroids for severe cases.
• Exclusions under appropriate-use recommendations: more than 4 microhaemorrhages, superficial siderosis, prior lobar haemorrhage, significant white matter disease, and anticoagulation. The Australian lecanemab PI contraindicates more than 2 microhaemorrhages.
• Australia: the TGA registered donanemab in 2025 for early symptomatic Alzheimer disease in APOE e4 non-carriers and heterozygotes, given only in specialist centres with the modified titration (TRAILBLAZER-ALZ 6), which lowers ARIA. Lecanemab was refused in October 2024 and the refusal was upheld on reconsideration in early 2025; after the Administrative Review Tribunal remitted the decision, the TGA registered lecanemab on 23 September 2025 for MCI or mild dementia due to Alzheimer disease, also excluding homozygotes. PBAC rejected donanemab in July 2025. Neither is PBS-listed (not on the November 2026 Schedule), so access is private and limited. Check current status before advising.
• The absolute benefit is about 4 to 6 months of delay over 18 months, against infusions, repeated MRIs, ARIA and cost. Fewer than 10% of people with Alzheimer disease meet trial criteria.

Pitfall: a stroke in a patient on an anti-amyloid antibody. Thrombolysis carries a high risk of haemorrhage; check for this treatment before giving it.

Behavioural and psychological symptoms

Look for pain, delirium and constipation first, and use non-drug strategies. Risperidone is limited to severe aggression or psychosis for up to 12 weeks. See Behavioural and psychological symptoms of dementia.

Complications and course

• Median survival after diagnosis is about 4 to 8 years, shorter with older age at diagnosis.
• Delirium with any illness or admission. See Delirium and acute confusion.
• Falls and hip fracture, weight loss, incontinence, seizures (in up to 10 to 20% late), carer exhaustion.
• Advanced disease: dysphagia, aspiration pneumonia and recurrent infection are the usual terminal events. PEG feeding doesn't prolong life or prevent aspiration; offer careful hand feeding and palliative care.
• Plan care early. Deprescribe statins, bisphosphonates and cholinesterase inhibitors as goals change.

Pitfalls

• Diagnosing Alzheimer disease during delirium.
• Missing Lewy body disease (fluctuation, hallucinations, REM sleep behaviour disorder, parkinsonism) and then giving haloperidol.
• Treating a low-normal B12 as the cause of established dementia.
• Starting donepezil without checking the pulse and ECG.
• Stopping a tolerated cholinesterase inhibitor just because decline continues.
• Assuming a positive amyloid PET in an 80-year-old proves Alzheimer disease is causing the symptoms. Amyloid positivity is common in cognitively normal older people.
• Offering an anti-amyloid antibody without APOE testing or to someone on an anticoagulant.
• Leaving legal and advance care planning until capacity has gone.