Alzheimer disease and other dementias

Overview

Dementia is a syndrome, not one disease. It means:

• an acquired decline in two or more cognitive domains (usually including memory: also language, executive function, visuospatial skills, praxis),
• severe enough to impair social or occupational function,
• and chronic, with clear consciousness, which separates it from delirium.

It is mainly a disease of age: about 6% of people over 65 and about 20% over 85 are affected. Alzheimer disease (AD) is by far the commonest cause.

Dementia versus delirium versus depression

Causes of dementia

Assessment

• History from a relative is essential; patients often minimise problems or turn to the relative to answer ("head-turning sign").
• Bedside tests: the mini-mental state examination (MMSE) (out of 30; insensitive to mild and frontal deficits) and the Addenbrooke's Cognitive Examination; clock drawing for parietal function; verbal fluency for frontal function; frontal release signs (grasp, pout, palmomental).
• Routine blood tests: full blood count, ESR, B12 and folate, thyroid function, urea and electrolytes, calcium, glucose, liver tests; syphilis and HIV serology where relevant.
• Brain imaging: CT excludes tumour, subdural and hydrocephalus; MRI is preferred to show patterns of atrophy and vascular damage.
• Selected patients: CSF (tau raised, Aβ42 low in AD; 14-3-3 protein and RT-QuIC in CJD), EEG, genetic tests, amyloid PET.

Mild cognitive impairment is memory loss beyond normal ageing without functional loss; about 10–15% a year progress to AD.

Alzheimer disease

Pathology

• Extracellular β-amyloid (Aβ42) plaques in the cortex, formed when amyloid precursor protein (APP) is cut by β- and γ-secretase.
• Intracellular neurofibrillary tangles of hyperphosphorylated tau.
• Neuronal and synaptic loss, starting in the hippocampus and medial temporal lobe, later generalised cortical atrophy with enlarged ventricles.
• Cholinergic deficit: loss of neurones in the nucleus basalis of Meynert (basal forebrain), which is why cholinesterase inhibitors help.
• Amyloid may also deposit in vessel walls (amyloid angiopathy, causing lobar haemorrhage).

Risk factors and genetics

• Age (the strongest); a first-degree relative roughly doubles the risk; head injury; vascular risk factors.
• ApoE4 allele: one copy increases risk 2–3 times, two copies 6–8 times.
• Early-onset familial AD (autosomal dominant, about 1% of cases): mutations in APP (chromosome 21), presenilin-1 (the commonest, half of monogenic cases) and presenilin-2.
• Down syndrome: an extra copy of the APP gene on chromosome 21 leads to early AD.

Clinical features

• Insidious loss of recent (episodic) memory with relative sparing of distant memories: repeating questions, misplacing things, forgetting appointments.
• Language: word-finding difficulty (anomia), later poor comprehension.
• Apraxia (cannot dress or use objects), agnosia (fails to recognise objects or faces), visuospatial problems (gets lost in familiar places).
• Executive problems: planning, managing money.
• Personality and social behaviour are preserved until late; motor function stays good, so patients wander.
• Late: incontinence, sleep-wake reversal, myoclonus, seizures, swallowing difficulty; death often from aspiration pneumonia.
• Gradual progression over about a decade.

Investigations

MRI: hippocampal and medial temporal lobe atrophy, later generalised atrophy. Imaging may be normal early. Diagnosis is clinical, backed by cognitive testing and imaging; definite diagnosis is histological.

Treatment

• Benefit is modest and symptomatic (about 1–2 MMSE points); none of these drugs stops progression.
• Cholinesterase inhibitors do not help frontotemporal or pure vascular dementia.
• Non-drug care: keep the person at home and in routine, support carers, treat depression, address driving, finances and power of attorney.
• Antipsychotics increase the risk of stroke and death in dementia; use only as a last resort for severe distress or danger, at the lowest dose and for the shortest time.

Other important dementias

Vascular dementia

• Second commonest; due to multiple infarcts, small-vessel disease or a strategic stroke. Often mixed with AD.
• Stepwise deterioration, history of strokes or TIAs, vascular risk factors.
• Focal neurological signs, pyramidal signs, gait disturbance, early urinary incontinence, emotional lability.
• MRI: infarcts and widespread white matter (small-vessel) change.
• Management: control vascular risk factors (blood pressure, diabetes, lipids, smoking, antiplatelet where indicated).

Dementia with Lewy bodies (DLB)

• Fluctuating cognition and alertness, recurrent well-formed visual hallucinations (people, animals), REM sleep behaviour disorder, parkinsonism; memory may be preserved early.
• Cortical Lewy bodies (α-synuclein).
• Severe sensitivity to antipsychotics (rigidity, falls, sudden decline, even death): avoid haloperidol.
• Responds well to cholinesterase inhibitors (rivastigmine, donepezil).

Frontotemporal dementia (Pick disease)

• Younger onset (usually under 65), often a family history (about 25%: tau, progranulin, C9orf72).
• Asymmetric frontal and temporal lobe atrophy; pathology with tau, TDP-43 or FUS inclusions (Pick bodies in classic Pick disease).
• Behavioural variant: early personality change, disinhibition, apathy, loss of empathy, compulsive behaviour, change in eating habits; memory relatively preserved early.
• Language variants: semantic dementia (fluent speech that has lost meaning) and progressive non-fluent aphasia.
• Overlap with MND in about 10%.
• No specific treatment; cholinesterase inhibitors do not help.

Creutzfeldt-Jakob disease (prion disease)

• Caused by misfolded prion protein (PrPSc) that converts the normal protein, causing spongiform change.
• Sporadic CJD (commonest; over 50; about 1 per million): rapidly progressive dementia with myoclonus (in about 90%), ataxia and visual problems; death usually within 6 months.
• Iatrogenic: neurosurgical instruments (prions resist sterilisation), corneal grafts, dura mater, cadaveric growth hormone.
• Variant CJD: linked to BSE (eating infected beef); younger patients (mean age about 29), psychiatric onset, painful sensory symptoms, longer course; tonsil biopsy can confirm.
• Tests: MRI (cortical ribboning, basal ganglia signal; pulvinar sign in variant CJD), EEG (periodic sharp-wave complexes in sporadic CJD), CSF 14-3-3 protein and the very sensitive RT-QuIC assay.
• No cure.

Other causes in brief

• Huntington disease: autosomal dominant CAG repeat on chromosome 4; chorea, psychiatric change and dementia in mid-life; caudate atrophy.
• HIV-associated dementia, neurosyphilis (general paralysis of the insane; Argyll Robertson pupils).
• Alcohol-related brain damage and Korsakoff syndrome (see the chapter on B12 deficiency and Wernicke-Korsakoff).

Quick revision

• Dementia: acquired, chronic, multi-domain cognitive loss with impaired function and clear consciousness.
• Commonest causes: Alzheimer, then vascular, Lewy body, frontotemporal.
• AD: amyloid plaques, tau tangles, hippocampal atrophy, nucleus basalis cholinergic loss; recent memory first.
• Genetics: ApoE4 (risk), APP (chromosome 21, Down syndrome), presenilin-1 and 2 (early onset).
• Treatment: donepezil, rivastigmine, galantamine (mild-moderate; check ECG); memantine (NMDA antagonist; moderate-severe).
• DLB: fluctuations, visual hallucinations, parkinsonism, antipsychotic sensitivity.
• FTD: young, personality change and disinhibition, memory spared early.
• CJD: rapid dementia, myoclonus, periodic EEG, CSF 14-3-3, death within months.
• Always check B12, thyroid, calcium, glucose, syphilis/HIV and a brain scan.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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