Dementia syndromes - Alzheimer disease
Description
- Commonest dementia - ~60-70% of all cases
- Insidious, progressive, amnestic onset: episodic memory (hippocampal) first, then language, visuospatial, executive, praxis
- Repetitive questioning, misplacing objects, losing the thread, disorientation to time
- Anosognosia - the patient minimises; the informant history is the diagnosis
Atypical (non-amnestic) presentations - younger onset, frequently missed
- Posterior cortical atrophy - visuospatial failure, difficulty reading/dressing/driving with normal eyes; often referred to ophthalmology first
- Logopenic variant primary progressive aphasia - word-finding pauses, impaired sentence repetition
- Frontal/dysexecutive variant - mimics bvFTD
Late features
- Apraxia, agnosia, incontinence, myoclonus, seizures, gait disturbance, mutism, dysphagia
- Early gait disorder, falls, incontinence or hallucinations point AWAY from Alzheimer disease
Epidemiology
- Prevalence doubles every ~5 yr after age 65: ~1-2% at 65, ~10% at 75-80, ~30-40% over 85
- F>M (partly longevity, partly biological)
- ~450,000 Australians with dementia; dementia is the leading cause of death in Australian women and the second overall
- <5% is early onset (<65); ~1% of all AD is autosomal dominant
- Higher prevalence and earlier onset in Aboriginal and Torres Strait Islander communities
Aetiopathogenesis
The two proteins
- Extracellular beta-amyloid -> neuritic plaques
- APP cleaved by beta- then gamma-secretase -> Abeta42 -> oligomers -> plaques
- Intracellular hyperphosphorylated tau -> neurofibrillary tangles
- Tangles are not specific - also in other tauopathies (PSP, CBD, FTD, CTE)
- Tangle burden (Braak staging), not plaque burden, correlates with cognitive decline
- Braak: transentorhinal -> limbic -> neocortical
- Downstream: synaptic loss, cholinergic neuron loss in the nucleus basalis of Meynert (the rationale for cholinesterase inhibitors), glutamatergic excitotoxicity, neuroinflammation, medial temporal then parietotemporal atrophy
Genetics
| Gene | Effect | |
|---|---|---|
| Autosomal dominant, early onset (<65) | APP (21), PSEN1 (14, commonest), PSEN2 (1) | Near-100% penetrance; onset 30s-50s |
| Risk gene | APOE e4 | Heterozygote ~3x, homozygote ~12-15x; lowers age of onset |
| Protective | APOE e2 |
- Trisomy 21 -> triple APP dosage -> almost universal AD pathology by age 40; screen for dementia from the late 30s in Down syndrome
- APOE genotyping is not a diagnostic test - but it now matters for anti-amyloid therapy eligibility and ARIA risk
Modifiable risk - ~45% of dementia is attributable to 14 modifiable factors (Lancet Commission 2024)
- Early life: less education
- Midlife: hearing loss, high LDL cholesterol, hypertension, obesity, alcohol excess, traumatic brain injury, physical inactivity
- Later life: smoking, depression, social isolation, diabetes, air pollution, untreated vision loss
Diagnosis
Clinical diagnosis. Biomarkers confirm the pathology; they do not replace the history.
A. History - from the patient AND an informant separately
- Onset, tempo, first-affected domain, functional impact (IADLs before ADLs: finances, medications, driving, cooking)
- Vascular risk, alcohol, head injury, depression, sleep, hearing and vision, drugs (anticholinergic burden), family history
- Delirium, depression and drugs must be excluded before diagnosing dementia
B. Cognitive testing
- MoCA (more sensitive for MCI and executive dysfunction; /30, <26 abnormal), MMSE (/30, poor for executive/visuospatial), ACE-III (/100, best for subtyping), RUDAS (validated across cultures and low literacy)
- KICA-Cog for Aboriginal and Torres Strait Islander patients
- Adjust for education, language, sensory impairment - an uncorrected hearing deficit produces a false-positive score
- Functional scale (IADL), carer-report scale
C. Exclude reversible and contributing causes - in everyone
- FBE, UEC, LFT, calcium, glucose/HbA1c, TSH, B12, folate
- Syphilis serology and HIV if risk factors; routine screening is no longer standard
- Depression screen (GDS), sleep apnoea, hearing/vision assessment, medication review
D. Structural imaging - CT or preferably MRI
- Medial temporal/hippocampal atrophy (supportive, not diagnostic - present in normal ageing too)
- Mainly excludes: subdural, tumour, hydrocephalus (NPH), extensive small vessel disease, stroke
E. Molecular biomarkers - specialist settings
- FDG-PET: temporoparietal + posterior cingulate/precuneus hypometabolism
- Contrast with DLB: occipital hypometabolism with the cingulate island sign (preserved posterior cingulate)
- Contrast with FTD: frontal and anterior temporal hypometabolism
- Amyloid PET - high negative predictive value; positive in ~30% of cognitively normal over-75s, so a positive scan alone does not diagnose dementia
- CSF: low Abeta42 (or low Abeta42/40 ratio) + high total tau and p-tau181
- Plasma biomarkers - the practice change: p-tau217 performs comparably to CSF for amyloid pathology and is entering specialist workup
- Not for primary-care screening or asymptomatic people
- Tc-99m HMPAO SPECT - regional perfusion; largely superseded by FDG-PET
- DaT SPECT to exclude DLB where parkinsonism is present
Distinguish from
| Discriminator | |
|---|---|
| DLB | Fluctuation, visual hallucinations, RBD, parkinsonism, neuroleptic sensitivity |
| Vascular | Stepwise, early gait/executive change, focal signs, vascular imaging |
| bvFTD | Early personality change, disinhibition, hyperorality, apathy; memory relatively preserved |
| NPH | Gait apraxia first, then urinary incontinence, then cognition |
| Depression ("pseudodementia") | "Don't know" answers, low effort, preserved cues, subacute onset |
| Delirium | Acute, fluctuating, inattention, altered conscious level |
Management
A. Non-pharmacological - the foundation
- Cognitive stimulation therapy, structured exercise, social engagement, occupational therapy home assessment
- Treat hearing and vision loss - hearing aids are among the highest-yield interventions
- Carer education and support; My Aged Care/ACAT assessment, Dementia Australia, respite, carer payments
- Advance care planning and enduring guardianship/power of attorney while capacity is retained
- *Driving: mandatory notification in some jurisdictions; assess and report per Austroads Assessing Fitness to Drive*** - moderate or severe dementia is incompatible with driving
B. Cognitive symptomatic therapy
- Cholinesterase inhibitors - donepezil, rivastigmine, galantamine for mild-moderate AD
- Modest symptomatic benefit (~ equivalent to 6-12 months' delay); no effect on progression
- PBS: initiation requires MMSE >=10 (or an equivalent instrument) with documented benefit at review
- Adverse: bradycardia and syncope (ECG before starting; check for AV block), nausea, diarrhoea, weight loss, vivid dreams, muscle cramps, urinary frequency
- Rivastigmine patch if GI intolerance
- Memantine (NMDA antagonist) for moderate-severe disease, or when cholinesterase inhibitors are not tolerated
- *Avoid anticholinergics - oxybutynin, amitriptyline, promethazine, older antihistamines; they directly oppose the treatment and worsen cognition*
C. Anti-amyloid monoclonal antibodies - a genuinely new class
- Lecanemab TGA-approved (Sept 2025) for MCI or mild dementia due to AD, in ApoE e4 non-carriers and heterozygotes only
- *ApoE e4 homozygotes excluded - unacceptable ARIA risk*
- Requires confirmed amyloid pathology (PET or CSF), IV infusion, serial MRI monitoring for ARIA (amyloid-related imaging abnormalities: ARIA-E oedema, ARIA-H haemorrhage)
- Avoid anticoagulation; exclude significant cerebral amyloid angiopathy and microhaemorrhages
- Effect size is modest (~25-30% slowing of decline over 18 months, of debated clinical significance) at high cost and significant monitoring burden
- Access in Australia is limited and largely not PBS-subsidised - discuss realistically
D. Behavioural and psychological symptoms (BPSD)
- *Look for a cause first* - pain, constipation, urinary retention, infection, drugs, boredom, fear, sensory deprivation, change of environment
- Non-pharmacological: routine, orientation, music, tailored activity, carer communication training
- Antipsychotics only for severe distress, aggression or psychosis with risk of harm
- Risperidone is the only PBS-approved agent, low dose, maximum 12 weeks, with documented review
- *Increased mortality and stroke risk; avoid entirely in DLB and Parkinson disease dementia*
- Depression: SSRI (modest evidence in dementia); avoid benzodiazepines
- Minimise chemical and physical restraint - reportable in Australian residential aged care
E. Risk factor modification
- Treat hypertension, diabetes, lipids; exercise, smoking cessation, alcohol reduction, hearing aids, social engagement
- Most effective in midlife; still worth doing after diagnosis
F. Late disease
- Palliative approach: comfort, oral feeding assistance
- *PEG feeding in advanced dementia does not prolong life, prevent aspiration or improve pressure areas* - do not offer
- Antibiotics, admission and resuscitation decisions revisited against the advance care plan
Associations
- Down syndrome - near-universal AD pathology by the 4th-5th decade
- APOE e4; family history
- Cerebral amyloid angiopathy - lobar haemorrhage, ARIA risk
- Mixed Alzheimer + vascular pathology - the commonest pathology at autopsy in the very old
- Depression (both a risk factor and a prodrome), apathy
- Hearing and vision impairment
- Delirium - an episode of delirium is a marker of, and a risk factor for, dementia
- Weight loss, sarcopenia, falls, fracture
- Seizures and myoclonus in advanced disease
- Obstructive sleep apnoea, traumatic brain injury
Natural history & complications
- Median survival ~7-10 yr from diagnosis (shorter with older age at onset, male sex, comorbidity)
- MMSE falls ~2-4 points per year on average; plateaus and rapid declines both occur - a sudden change means delirium, not progression
- Trajectory: MCI -> mild -> moderate (ADL dependence, BPSD peak) -> severe (mutism, immobility, dysphagia)
- Death is usually from pneumonia (aspiration), other infection, or the complications of immobility
- ~10-15% of amnestic MCI converts to dementia per year
- Poor prognostic markers: rapid decline in the first year, early psychosis, weight loss, comorbid vascular disease
Monitor
- 6-monthly: cognition, function, weight, BPSD, medication review (deprescribe anticholinergics and sedatives)
- Carer strain, driving, safety, capacity, advance care plan review
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