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Dementia
9 notes available
1 Last Minute Review 2 Alzheimer Disease 3 Frontotemporal Dementia 4 Lewy Body & Parkinson Dementia 5 Vascular Cognitive Impairment 6 Rapidly Progressive Dementias 7 Reversible & Secondary Dementias 8 Mild Cognitive Impairment & Dementia Workup 9 Behavioral & Psychiatric Features
Clinical › Dementia

Alzheimer Disease

Alzheimer Disease

What You'll Learn

  • Aβ42 & Tau: amyloid plaques (Aβ42) are the pathologic hallmark; neurofibrillary tangles (hyperphosphorylated tau) correlate with clinical severity
  • Biomarker framework (A/T/N): Amyloid (CSF Aβ42↓, amyloid PET+), Tau (CSF p-tau↑, tau PET+), Neurodegeneration (CSF t-tau↑, FDG-PET↓, MRI atrophy)
  • Genetics: Early-onset AD — PSEN1 (chr 14, most common familial), APP (chr 21), PSEN2 (chr 1); Late-onset — APOE ε4 (strongest genetic risk factor, NOT deterministic)
  • Imaging signature: medial temporal/hippocampal atrophy on MRI; temporoparietal hypometabolism on FDG-PET; posterior cingulate involved early
  • Braak NFT staging: transentorhinal (I–II) → limbic (III–IV) → neocortical (V–VI); correlates with clinical progression
  • Treatment: cholinesterase inhibitors (mild–moderate), memantine (moderate–severe), anti-amyloid antibodies (lecanemab, donanemab) — monitor for ARIA
  • Atypical variants: posterior cortical atrophy (visual), logopenic PPA (language), frontal variant — all have AD pathology with different cortical targets
HighYield Pearls
  • ATN biomarker triad: A+ (amyloid PET or CSF Aβ42/40↓) + T+ (CSF p-tau181/p-tau217 or tau PET) + N (MRI hippocampal atrophy or FDG-PET temporoparietal hypometabolism) — A+T+ defines biologically diagnosed AD; A− rules AD off the continuum regardless of T/N
  • Anti-amyloid mAbs (lecanemab, donanemab): FDA-approved for early symptomatic AD with amyloid+ biomarkers; APOE ε4 genotyping SHOULD be performed before treatment per FDA labels to counsel ARIA risk (ε4 homozygotes have the highest ARIA-E [~40% with donanemab] and ARIA-H risk) — not an absolute prerequisite; if not performed, treatment is not automatically prohibited but ARIA risk counseling is incomplete. Aducanumab withdrawn (Jan 2024)
  • PSEN1 is the most common autosomal-dominant EOAD gene (chr 14, not APP); APP duplications → AD + CAA; trisomy 21 (Down syndrome) → near-universal AD pathology by age 40
  • APOE ε4 is a RISK FACTOR, not deterministic — heterozygote 3–4×, homozygote ~12–15× (Fortea 2024 suggests ε4/ε4 may be a genetic form of AD); ε2 protective for AD but ↑ CAA hemorrhage risk
  • Logopenic PPA = AD pathology in 70–90% (NOT FTD); impaired sentence repetition + word-finding pauses with preserved grammar/comprehension
  • PCA (Benson syndrome) = visual variant of AD: Balint triad (simultanagnosia + optic ataxia + oculomotor apraxia) ± Gerstmann (left angular gyrus: finger agnosia + acalculia + agraphia + L/R confusion); memory preserved early
  • Behavioral/dysexecutive (frontal) AD mimics bvFTD but is A+T+ on biomarkers — classic pitfall; biomarkers are the discriminator
  • CSF t-tau markedly elevated (>10×) → think CJD, not AD; CSF Aβ42 is LOW in AD (sequestered in plaques) while p-tau is HIGH
  • Neuritic plaques (CERAD) + Braak NFT staging required for definite neuropathologic AD diagnosis — diffuse plaques do NOT count; NFT burden (not amyloid load) correlates with clinical severity
  • Always exclude reversible mimics before diagnosing neurodegenerative dementia: B12, TSH, structural disease (NPH, subdural hematoma), pseudodementia (depression). Add RPR/VDRL and HIV when history, age, tempo, exam, or risk factors support them — per AAN 2001 (reaffirmed), routine syphilis screening is not justified without risk factors or suggestive evidence
🔍 Quick ReferenceClinical · Imaging / biomarkers · Pathology / genetics
Clinical phenotype
  • Amnestic progressive episodic memory loss + anomia + getting lost in familiar places → Classic (typical) AD
  • Simultanagnosia + optic ataxia + oculomotor apraxia (Balint triad) → Posterior cortical atrophy (PCA / Benson syndrome) — visual variant of AD
  • Finger agnosia + acalculia + agraphia + L/R confusion (Gerstmann syndrome) → Left angular gyrus involvement (often PCA / AD)
  • Word-finding pauses + impaired sentence repetition with preserved grammar & single-word comprehension → Logopenic PPA (lvPPA) — usually AD pathology
  • Frontal/behavioral mimic of bvFTD with positive AD biomarkers → Behavioral/dysexecutive (frontal variant) AD
  • Preserved insight early + sundowning + Capgras delusion → Alzheimer disease
  • Apperceptive prosopagnosia + alexia + environmental disorientation → PCA (visual variant AD)
Imaging / biomarkers
  • Hippocampal/medial temporal lobe atrophy on coronal MRI (Scheltens MTA scale ≥2) → Alzheimer disease
  • Bilateral temporoparietal + posterior cingulate/precuneus hypometabolism on FDG-PET with frontal sparing → Alzheimer disease
  • Diffuse cortical amyloid uptake on PET (Pittsburgh compound B / florbetapir / flutemetamol / florbetaben) → Amyloid+ (AD continuum)
  • Flortaucipir (tau PET) uptake in posterior cingulate / parietal / temporal cortex → AD-type 3R/4R PHF tau
  • CSF Aβ42 LOW, Aβ42/Aβ40 ratio LOW, p-tau181/p-tau217 HIGH → Alzheimer disease
  • Plasma p-tau217 elevated (Core 1 biomarker, 2024 NIA-AA) → Alzheimer disease
  • FLAIR sulcal/parenchymal hyperintensity after anti-amyloid mAb → ARIA-E (vasogenic edema)
  • T2*/SWI microbleeds or cortical superficial siderosis after anti-amyloid mAb → ARIA-H
  • Occipitoparietal atrophy / hypometabolism with preserved hippocampi → PCA (visual variant AD)
  • Lobar microbleeds + cortical superficial siderosis + lobar ICH in elderly (Boston criteria v2.0) → Cerebral amyloid angiopathy (CAA)
Pathology / genetics
  • Extracellular Aβ42 neuritic plaques + intraneuronal NFTs (paired helical filaments, mixed 3R+4R hyperphosphorylated tau) + neuropil threads → Alzheimer disease
  • Braak NFT staging: entorhinal/transentorhinal (I–II) → limbic (III–IV) → neocortical (V–VI) → AD tau spread (bottom-up)
  • Thal amyloid phases 1→5: neocortex → allocortex → diencephalon → brainstem → cerebellum → AD amyloid spread (top-down)
  • Granulovacuolar degeneration + Hirano bodies in hippocampal CA1 → Alzheimer disease (non-specific but classic)
  • Aβ40 deposition in cortical/leptomeningeal vessel walls → lobar ICH + cortical siderosis → Cerebral amyloid angiopathy (CAA)
  • APP duplication / mutation on chr 21 (also trisomy 21 / Down syndrome) → Early-onset AD by 40s ± CAA
  • PSEN1 (chr 14) — most common autosomal-dominant EOAD, near-100% penetrance, may include seizures / myoclonus / spastic paraparesis → Familial AD
  • PSEN2 (chr 1) — rare, Volga German families, later onset, incomplete penetrance → Familial AD
  • APOE ε4 heterozygote 3–4×, ε4/ε4 homozygote ~12–15× risk → Strongest sporadic AD risk factor (impairs Aβ clearance)
  • APOE ε2 → Protective for AD but increases CAA-related lobar hemorrhage risk
  • TREM2 R47H variant, ABCA7 variants → Mild sporadic AD risk modifiers
  • NIA-AA "ABC" score: A = Thal amyloid phase, B = Braak NFT stage, C = CERAD neuritic plaque score → Definite neuropathologic AD diagnosis
Pathophysiology & Amyloid Cascade Hypothesis

APP Processing

  • Amyloid precursor protein (APP): transmembrane protein encoded on chromosome 21; normal function includes synaptic plasticity and neuronal survival
  • Non-amyloidogenic pathway: α-secretase cleaves APP within the Aβ domain → soluble APPα (neuroprotective) → no Aβ produced
  • Amyloidogenic pathway: β-secretase (BACE1) then γ-secretase cleave APP → Aβ peptides released
  • Aβ40 vs. Aβ42: Aβ42 is more hydrophobic, more prone to aggregation, and is the predominant species in amyloid plaques
  • γ-secretase complex contains presenilin 1 or 2 (PSEN1/PSEN2) — mutations increase Aβ42/Aβ40 ratio

Amyloid Cascade Hypothesis

  • Aβ42 monomers → oligomers (most toxic species) → protofibrils → fibrils → insoluble amyloid plaques
  • Soluble Aβ oligomers impair synaptic function, induce oxidative stress, trigger neuroinflammation (microglial activation)
  • Amyloid deposition → downstream tau hyperphosphorylation → neurofibrillary tangles (NFTs) → neuronal death
  • Key distinction: amyloid plaques correlate poorly with clinical severity; NFT burden correlates with cognitive decline

Tau Pathology

  • Tau is a microtubule-associated protein; normal function = stabilizes axonal microtubules
  • Hyperphosphorylation → tau detaches from microtubules → forms paired helical filaments (PHFs) → NFTs
  • NFTs spread in a stereotyped pattern (Braak staging) from entorhinal cortex → hippocampus → neocortex
  • Prion-like propagation: tau spreads trans-synaptically along connected neural networks
💎 Board Pearl
  • Aβ plaques are necessary but not sufficient for AD diagnosis — cognitively normal elderly can have extensive amyloid
  • NFT burden (not amyloid plaque load) best correlates with clinical severity and cognitive decline
  • γ-secretase contains presenilin — this links PSEN1/PSEN2 mutations directly to increased Aβ42 production
  • Down syndrome (trisomy 21) → extra copy of APP gene → virtually all develop AD pathology by age 40
🔒

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