Dementia & Alzheimer's Disease

Dementia is an acquired, progressive, global decline in cognition severe enough to impair daily functioning, occurring in a setting of clear consciousness. Alzheimer's disease (AD) is the commonest cause (~60-70%). This topic is a perennial NEET PG favourite for neuropathology buzzwords, the cholinergic hypothesis, dementia subtype differentiation, and cholinesterase-inhibitor pharmacology.

Definition & core concept

Dementia (now termed Major Neurocognitive Disorder in DSM-5) requires:

1. Significant decline in one or more cognitive domains (memory, executive function, language, attention, perceptual-motor, social cognition).
2. Deficits interfere with independence in everyday activities.
3. Not occurring exclusively during a delirium.
4. Not better explained by another psychiatric disorder.

High-yield: The single most important examination distinction is dementia vs delirium. Dementia = chronic, insidious, clear sensorium, stable attention, irreversible (usually). Delirium = acute, fluctuating, clouded consciousness, impaired attention, often reversible. Attention is the bedside discriminator: preserved early in dementia, grossly impaired in delirium.

Mild Neurocognitive Disorder (≈ Mild Cognitive Impairment, MCI) = decline present but independence is retained; ~10-15%/year convert to dementia (amnestic MCI → AD).

Classification of dementias

Category	Examples	Key feature
Cortical (degenerative)	Alzheimer's, frontotemporal dementia	Amnesia, aphasia, apraxia, agnosia
Subcortical	Parkinson's, Huntington's, HIV, PSP, vascular (lacunar)	Slowed processing, apathy, movement disorder, memory recall improves with cues
Vascular	Multi-infarct, Binswanger	Stepwise decline, focal signs
Lewy body spectrum	DLB, Parkinson's dementia	Fluctuation, visual hallucinations, parkinsonism
Prion	Creutzfeldt-Jakob	Rapidly progressive + myoclonus
Reversible	B12 deficiency, hypothyroidism, NPH, neurosyphilis, subdural haematoma, depression	Treatable — must be excluded

High-yield: Always screen for reversible causes before labelling a dementia "degenerative." Classic exam list — B12 deficiency, hypothyroidism, neurosyphilis, normal pressure hydrocephalus (NPH), chronic subdural haematoma, HIV, and pseudodementia (depression). Mnemonic: "DEMENTIA" for reversibles — Drugs, Emotional (depression), Metabolic/endocrine, Eyes/ears (sensory), Nutritional (B12/thiamine), Tumour/trauma, Infection, Alcohol.

Alzheimer's disease — etiology & pathophysiology

AD is a neurodegenerative tauopathy/amyloidopathy. Risk rises sharply with age; commonest cause of dementia overall.

Risk & genetics

• Strongest non-modifiable risk factor: advancing age.
• APOE ε4 allele — strongest genetic risk for late-onset/sporadic AD (dose-dependent). APOE ε2 is protective.
• Early-onset familial AD (autosomal dominant): mutations in APP (chromosome 21), Presenilin-1 (PSEN1, chr 14 — commonest familial) and Presenilin-2 (PSEN2, chr 1).
• Down syndrome (trisomy 21) → extra APP gene dose → almost universal AD-type pathology by age 40.

Neuropathology (the buzzword block)

Lesion	Composition	Notes
Senile (neuritic) plaques	Extracellular β-amyloid (Aβ42) from APP cleaved by β- and γ-secretase	Aβ deposition is the earliest event (amyloid cascade hypothesis)
Neurofibrillary tangles (NFTs)	Intracellular hyperphosphorylated tau → paired helical filaments	NFT burden correlates best with clinical severity
Cerebral amyloid angiopathy	Aβ in vessel walls	Lobar haemorrhage risk
Granulovacuolar degeneration / Hirano bodies	Hippocampal neurons	Supportive findings

High-yield: Plaques are extracellular amyloid; tangles are intracellular tau. Tangle density (not plaque density) correlates best with degree of dementia. Pathology begins in the entorhinal cortex/hippocampus → spreads to neocortex.

Macroscopic: diffuse cortical atrophy, widened sulci, narrowed gyri, dilated ventricles (hydrocephalus ex vacuo); earliest and most marked atrophy in medial temporal lobe / hippocampus.

The cholinergic hypothesis — Degeneration of cholinergic neurons in the nucleus basalis of Meynert → loss of acetylcholine (reduced choline acetyltransferase) in cortex and hippocampus → memory deficit. This is the rationale for cholinesterase inhibitors.

High-yield: Cell of origin of the cortical cholinergic deficit in AD = nucleus basalis of Meynert. The enzyme reduced = choline acetyltransferase (ChAT).

Clinical features of AD

Progression is insidious and steadily progressive (contrast vascular's stepwise course).

Flow of cognitive decline: Anterograde episodic memory loss (recent > remote) → executive dysfunction & word-finding (anomia) → visuospatial disorientation / getting lost → apraxia, agnosia, language breakdown → behavioural symptoms (BPSD): agitation, wandering, psychosis, sundowning → akinetic mutism, incontinence, total dependence.

• Early sign: loss of recent memory (hippocampal); remote/procedural memory relatively spared until late.
• The classic cortical tetrad: the 4 A's → Amnesia, Aphasia, Apraxia, Agnosia.
• Insight is lost early; primary motor/sensory and visual function preserved until late.
• BPSD (Behavioural & Psychological Symptoms of Dementia): depression, delusions (theft, infidelity), hallucinations, agitation, sundowning (worsening confusion in evening).

Diagnosis & investigation of choice

AD is fundamentally a clinical diagnosis; investigations exclude reversible causes and support the diagnosis.

Cognitive screening tools

Test	Max score	Cut-off / notes
MMSE (Folstein Mini-Mental State Examination)	30	<24 suggests cognitive impairment; 21-24 mild, 10-20 moderate, <10 severe. Poor for frontal/executive & visuospatial function
MoCA (Montreal Cognitive Assessment)	30	<26 abnormal; more sensitive than MMSE for MCI and executive deficits; includes trail-making, clock-draw, abstraction
Clock-drawing test	—	Quick visuospatial + executive screen
AMTS / Mini-Cog	—	Rapid bedside screens

High-yield: MMSE max = 30; cut-off for impairment <24. MoCA is more sensitive than MMSE for mild cognitive impairment and frontal-executive dysfunction. MMSE is relatively education-biased and misses early/executive deficits.

Investigations to exclude reversible causes (mandatory work-up): CBC, serum B12 and folate, TSH, electrolytes/calcium, LFT/RFT, glucose, VDRL/TPHA (neurosyphilis), HIV serology where indicated.

Neuroimaging — investigation of choice = MRI brain.

• MRI: medial temporal lobe / hippocampal atrophy (AD); rules out tumour, subdural, infarcts, NPH.
• FDG-PET: temporoparietal hypometabolism (AD pattern); frontotemporal hypometabolism in FTD.
• Amyloid PET (PiB) and CSF biomarkers — ↓ Aβ42, ↑ total tau & phospho-tau — support AD; the "ATN" biomarker framework (Amyloid, Tau, Neurodegeneration).
• EEG: not routine; periodic sharp-wave complexes in CJD, generalised slowing in advanced dementia.

High-yield: CSF in AD → low Aβ42, high tau/phospho-tau. Definitive confirmation of AD is histopathology (plaques + tangles) — i.e. post-mortem/biopsy; clinically it remains "probable AD."

Management & drug of choice

There is no cure; aims are to slow decline, treat BPSD, and support carers.

Pharmacology — cholinesterase inhibitors (mild–moderate AD)

Drug	Key points
Donepezil	Once-daily, long t½, centrally selective; usable across mild→severe; first-line
Rivastigmine	Inhibits both acetyl- & butyrylcholinesterase; transdermal patch ↓ GI effects; approved in Parkinson's disease dementia
Galantamine	AChE inhibitor + nicotinic receptor modulation
Memantine	NMDA-receptor antagonist — for moderate–severe AD; can combine with a ChEI

High-yield: Drug class of choice for mild-to-moderate AD = cholinesterase inhibitors (donepezil/rivastigmine/galantamine). Memantine (NMDA antagonist) is for moderate-to-severe disease. Memantine reduces glutamate excitotoxicity.

Cholinesterase inhibitor adverse effects are predictably cholinergic: nausea, vomiting, diarrhoea, anorexia/weight loss, bradycardia & syncope (caution in sick-sinus/heart block), muscle cramps, vivid dreams.

Disease-modifying anti-amyloid monoclonals (newer): lecanemab and donanemab (anti-Aβ antibodies) modestly slow early AD; key toxicity = ARIA (Amyloid-Related Imaging Abnormalities — oedema/microhaemorrhage), higher in APOE ε4 carriers.

Managing BPSD: non-pharmacological first (routine, orientation, environment). For severe agitation/psychosis use low-dose atypical antipsychotics cautiously — note the black-box warning of increased mortality (stroke) in elderly dementia. Avoid antipsychotics in DLB (severe neuroleptic sensitivity). Treat coexisting depression with SSRIs; avoid strong anticholinergics (they worsen cognition).

Key differentials — dementia subtypes (most tested table)

Feature	Alzheimer's	Vascular	Lewy body (DLB)	Frontotemporal (Pick)
Onset/course	Insidious, gradual	Abrupt, stepwise	Fluctuating	Insidious, young (45-65)
Earliest deficit	Recent memory	Variable, focal	Visual hallucinations + fluctuating cognition	Personality / behaviour or language
Motor	Late	Focal signs, gait	Parkinsonism	Late
Hallmark	Plaques + NFTs; hippocampal atrophy	Infarcts, white-matter disease; vascular risk factors	α-synuclein Lewy bodies; REM sleep behaviour disorder; neuroleptic sensitivity	Tau/TDP-43 (Pick bodies); frontotemporal atrophy
Memory early on	Impaired	Patchy	Relatively spared early	Relatively spared early

High-yield (DLB triad): fluctuating cognition + recurrent visual hallucinations + spontaneous parkinsonism, plus REM sleep behaviour disorder and severe neuroleptic sensitivity. One-year rule: dementia before/within 1 year of parkinsonism = DLB; parkinsonism for >1 year first = Parkinson's disease dementia.

High-yield (FTD): Young onset, behavioural variant (disinhibition, apathy, hyperorality) or primary progressive aphasia; memory and visuospatial skills preserved early. Pathology = Pick bodies (tau) or TDP-43.

Normal Pressure Hydrocephalus (NPH) — classic reversible mimic. Triad → "Wet, Wacky, Wobbly" = urinary incontinence + dementia + gait apraxia (magnetic gait). Imaging: ventriculomegaly out of proportion to atrophy. Treatment: VP shunt; gait responds best.

Creutzfeldt-Jakob disease (CJD) — rapidly progressive dementia + myoclonus + ataxia; EEG periodic sharp waves; MRI cortical ribboning / pulvinar sign; CSF 14-3-3 protein & RT-QuIC; prion (PrP^Sc) aetiology.

Pseudodementia (depression) — older patient with apparent cognitive decline; "I don't know" answers, recent + remote memory equally affected, preserved orientation, complains more than deficit warrants, responds to antidepressants. Contrast true dementia where patients conceal deficits.

	True dementia (AD)	Pseudodementia (depression)
Onset	Insidious	Relatively abrupt
Mood	Variable, often unaware	Prominent depression, distress
Effort on testing	Tries, confabulates	"Don't know," poor effort
Memory	Recent ≫ remote loss	Recent = remote, inconsistent
Course at night	Sundowning worse	Often better

Complications

• Progressive total dependence, immobility, aspiration pneumonia (commonest cause of death).
• Falls and fractures, pressure sores, malnutrition, dehydration.
• BPSD → caregiver burnout, wandering/elopement, accidents.
• Adverse drug effects: antipsychotic-related stroke/mortality; cholinergic bradycardia/falls.
• Increased delirium risk superimposed on dementia during illness/hospitalisation.

Recently asked / exam angle

• Buzzword recall: "Extracellular amyloid" = senile plaque; "intracellular paired helical filaments/tau" = neurofibrillary tangle. Which correlates best with severity → NFTs/tangles.
• Nucleus basalis of Meynert as the source of the cholinergic deficit — recurring single-best-answer.
• MMSE max score (30) and cut-off; MoCA more sensitive for MCI — frequently tested values.
• Drug MOA matching: donepezil/rivastigmine/galantamine = AChE inhibitors; memantine = NMDA antagonist; rivastigmine also inhibits butyrylcholinesterase and is preferred in Parkinson's dementia.
• Genetics: PSEN1 = commonest familial early-onset; APOE ε4 = late-onset risk; Down syndrome → early AD via APP (chr 21).
• DLB: "fluctuating cognition + visual hallucinations + parkinsonism + neuroleptic sensitivity" — avoid typical antipsychotics.
• Reversible dementia vignette (B12/hypothyroid/NPH) — pick the treatable cause.
• CJD: rapidly progressive dementia + myoclonus + periodic EEG + 14-3-3.
• Investigation of choice: MRI; CSF pattern ↓Aβ42, ↑tau.

Rapid revision

1. Dementia = acquired global cognitive decline in clear consciousness; delirium = acute, fluctuating, with clouded consciousness and impaired attention.
2. Alzheimer's is the commonest dementia; earliest deficit = recent/episodic memory (hippocampus/entorhinal cortex).
3. Senile plaques = extracellular Aβ42; neurofibrillary tangles = intracellular hyperphosphorylated tau; tangle burden correlates best with severity.
4. Cholinergic deficit arises from the nucleus basalis of Meynert; ↓ choline acetyltransferase.
5. APOE ε4 = late-onset risk (ε2 protective); PSEN1/PSEN2/APP = familial early-onset; Down syndrome → early AD.
6. MMSE max 30, <24 abnormal; MoCA more sensitive for MCI and executive function.
7. Investigation of choice = MRI (medial temporal atrophy); CSF: low Aβ42, high tau/phospho-tau; definitive Dx = histopathology.
8. Mild–moderate AD → cholinesterase inhibitors; moderate–severe → memantine (NMDA antagonist).
9. ChEI side effects are cholinergic (GI upset, bradycardia, syncope); avoid anticholinergics.
10. Vascular dementia = stepwise decline with focal signs and vascular risk factors.
11. DLB triad = fluctuating cognition + visual hallucinations + parkinsonism (+ REM sleep behaviour disorder, neuroleptic sensitivity); 1-year rule separates DLB from Parkinson's dementia.
12. NPH = "wet, wacky, wobbly" (incontinence, dementia, magnetic gait) → reversible with VP shunt; CJD = rapid dementia + myoclonus + periodic EEG + 14-3-3 protein.