Pathophysiology of dementia

Definition

Dementia is a syndrome of acquired, progressive cognitive decline sufficient to impair function - with several distinct underlying pathologies producing overlapping but distinguishable clinical patterns

Alzheimer's disease is the most common cause overall; vascular dementia is the second most common (often co-existing with Alzheimer's pathology - "mixed dementia"); dementia with Lewy bodies and frontotemporal dementia are less common but clinically distinctive

Alzheimer's disease - extracellular amyloid-beta plaques and intracellular tau neurofibrillary tangles, with progressive neuronal loss beginning in the medial temporal lobe (hippocampus) - explains the early, prominent short-term memory impairment
Vascular dementia - cumulative ischaemic injury (multiple infarcts, or diffuse small vessel disease) - stepwise decline pattern (vs Alzheimer's gradual decline) and executive dysfunction often more prominent than memory loss early on
Dementia with Lewy bodies - alpha-synuclein-containing Lewy body inclusions - fluctuating cognition, visual hallucinations, parkinsonism, and marked antipsychotic sensitivity (a specific, dangerous trap)
Frontotemporal dementia - frontal/temporal lobe atrophy, often with tau or TDP-43 pathology - prominent personality/behavioural change or language impairment, often with relatively preserved memory early on, and a younger typical age of onset than Alzheimer's

Clinical pattern (memory-predominant vs executive/stepwise vs fluctuating with hallucinations vs behavioural/language-predominant) narrows the likely subtype; neuroimaging (atrophy pattern, vascular burden) and, increasingly, biomarkers (CSF or PET amyloid/tau) support diagnosis in ambiguous cases

Subtype affects management: cholinesterase inhibitors have the strongest evidence in Alzheimer's and Lewy body dementia; antipsychotics should be avoided or used with extreme caution in Lewy body dementia given the risk of severe, sometimes fatal neuroleptic sensitivity reactions
Vascular risk factor management (BP, lipids, glycaemic control) is specifically relevant to slowing vascular dementia progression, distinct from Alzheimer's-directed therapy

Mild cognitive impairment (a pre-dementia stage), Parkinson's disease (shares pathology with Lewy body dementia), cerebrovascular disease

Mixed pathology (e.g. concurrent Alzheimer's and vascular disease) is common, particularly in the oldest patients - a single "pure" pathological diagnosis is often an oversimplification, and management should address all contributing factors identified

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