382.1 🎓 醫孞生版

382.1.0.1 📌 䞀頁重點

382.1.0.1.1 Epidemiology
  • 60-80% of all dementia
  • ~ 6 million in US, > 50 million worldwide
  • Prevalence ~ 10% age 65, > 30% age 85
  • Women > men (longevity)
382.1.0.1.2 Pathology

382.1.1 Hallmarks

  • Amyloid-β plaques (Aβ42 oligomers most toxic)
  • Neurofibrillary tangles (hyperphosphorylated tau)
  • Neuronal loss
  • Synaptic loss
  • Gliosis
  • Cholinergic deficit (nucleus basalis Meynert)

382.1.2 Braak Staging

  • Stage I-II: entorhinal (transentorhinal) — preclinical
  • Stage III-IV: hippocampal/limbic — MCI to early
  • Stage V-VI: temporal/parietal/frontal/occipital — moderate to severe

382.1.3 Amyloid Hypothesis

  • Aβ accumulation → tau → neuronal death
  • Targeted by anti-amyloid therapies
382.1.3.0.1 Risk Factors

382.1.4 Non-Modifiable

  • Age (most important)
  • APOE ε4 genotype (1 copy 3x risk, 2 copies 8-12x)
  • Down syndrome (chromosome 21 — APP gene)
  • Female sex (post-65)
  • Family history
  • Genetic forms (APP, PSEN1, PSEN2 — early-onset, AD)

382.1.5 Modifiable

  • Cardiovascular risk (HTN, DM, smoking, dyslipidemia, obesity)
  • Low educational attainment (less cognitive reserve)
  • Head trauma
  • Depression
  • Hearing loss (consider hearing aids)
  • Social isolation
  • Physical inactivity
  • Sleep disorders (OSA, insufficient sleep)
  • Air pollution
  • Excessive alcohol
  • Lancet Commission 2024: 14 modifiable factors
382.1.5.0.1 Clinical Features

382.1.6 Cognitive Domains

Early (Mild): - Episodic memory (recent > remote) — hallmark - Anomia (word-finding) - Apraxia, agnosia - Visuospatial difficulty - Executive function (judgment, planning)

Moderate: - Disorientation - ADL impairment - Behavioral changes - Aphasia worsens - Some neurological signs

Severe: - IADL/BADL dependent - Mutism or severe aphasia - Bedbound - Incontinence - Myoclonus, seizures (some) - Cachexia

382.1.7 BPSD (Behavioral + Psychological Symptoms)

  • Agitation, aggression
  • Hallucinations, delusions
  • Depression, anxiety
  • Apathy
  • Wandering
  • Sleep disturbance
  • Sundowning

382.1.8 Atypical Presentations

  • Logopenic primary progressive aphasia (AD pathology)
  • Posterior cortical atrophy (visuospatial, Benson syndrome)
  • Frontal AD variant
  • Down syndrome AD
382.1.8.0.1 Diagnostic Framework

382.1.9 NIA-AA 2024 Revision

  • Biological diagnosis based on biomarkers (Aβ + tau)
  • AD continuum:
    • Preclinical AD (biomarker positive, normal cognition)
    • MCI due to AD (biomarker positive + MCI)
    • Dementia due to AD (biomarker positive + dementia)
  • Previously required clinical + biomarker
  • Now: biomarkers can diagnose AD

382.1.10 Biomarkers

CSF: - Aβ42 ↓ (deposited in plaques) - Aβ42/Aβ40 ratio ↓ - Total tau ↑ - Phosphorylated tau (p-tau 181, p-tau 217) ↑

Imaging: - Amyloid PET (florbetapir, florbetaben, flutemetamol, Pittsburgh compound B) - Tau PET (flortaucipir, others) - FDG-PET — temporoparietal hypometabolism - MRI — hippocampal/medial temporal atrophy, generalized

Plasma (emerging — important): - p-tau 217 (most accurate) - p-tau 181 - Aβ42/Aβ40 ratio - GFAP - NfL (neurodegeneration general) - Coming to clinical practice

382.1.11 Cognitive Tests

  • MMSE (Mini-Mental State Examination): 0-30
  • MoCA (Montreal Cognitive Assessment): 0-30 (more sensitive for MCI)
  • ADAS-Cog (for trials)
  • Neuropsychological testing

382.1.12 Imaging

  • MRI: hippocampal/medial temporal atrophy
  • FDG-PET: temporoparietal hypometabolism
  • Amyloid PET: clinical (especially before anti-amyloid Tx)
  • Tau PET: research mostly
382.1.12.0.1 MCI (Mild Cognitive Impairment)

382.1.13 Definition

  • Cognitive decline beyond aging
  • NOT functional impairment (preserved ADLs)
  • May or may not progress

382.1.14 Subtypes

  • Amnestic (memory) — most likely AD
  • Non-amnestic single-domain
  • Multiple-domain

382.1.15 Progression

  • ~ 10-15% per year progress to dementia
  • Amnestic MCI most likely AD
382.1.15.0.1 Treatment

382.1.16 Symptomatic

Cholinesterase Inhibitors (Mild-Moderate AD): - Donepezil (Aricept) 5-23 mg/d - Rivastigmine (Exelon) PO or patch - Galantamine (Razadyne) 8-24 mg/d - Modest cognitive benefit - Side effects: GI, bradycardia, sleep disturbance - Continue if benefit perceived (no clear stop criteria)

Memantine (NMDA Antagonist): - For moderate-severe AD - Can combine with cholinesterase inhibitor - 5-20 mg/d - Side effects: dizziness, confusion

382.1.17 Disease-Modifying (ANTI-AMYLOID mAbs)

Lecanemab (Leqembi) — FDA Jan 2023 (accelerated), Jul 2023 (full): - Anti-amyloid mAb (anti-protofibril) - For early AD (MCI + mild dementia) with confirmed amyloid - IV infusion every 2 weeks - Clarity AD trial: slowed cognitive decline ~ 27% (CDR-SB), modest absolute effect - ARIA-E (edema) 12-13%, ARIA-H (hemorrhage) 17% — most asymptomatic, but serious in some - APOE ε4 homozygous: highest ARIA risk - Pre-Tx: MRI baseline + monitoring - Cost: ~ $26,500/year (US)

Donanemab (Kisunla) — FDA July 2024: - Anti-amyloid mAb (targets pyroglutamate Aβ) - For early AD - IV monthly - TRAILBLAZER-ALZ 2 trial: slowed decline 35% iADRS, 22% CDR-SB - Treatment until amyloid cleared (some patients can stop) - ARIA risk - Faster amyloid clearance than lecanemab

Aducanumab (Aduhelm) — withdrawn from market 2024 due to controversies

382.1.18 Other

  • Manage CV risk factors aggressively
  • Address modifiable risks
  • Lifestyle (exercise, Mediterranean diet, MIND diet, cognitive engagement, social)
  • Treat sleep disorders
  • Sensory aids (hearing aids — important)
  • Caregiver support

382.1.19 BPSD

  • Non-pharmacologic first
  • Behavioral approaches
  • Address pain, infection, environment, medications
  • Brexpiprazole (Rexulti) FDA 2023 for AD agitation
  • Pharmacologic: cautious atypical antipsychotics (off-label, BBW)
  • Citalopram (CitAD trial)
  • Trazodone for sleep
  • AVOID benzodiazepines (worsen)

382.1.19.1 🩺 床邊速查

  • AD = 60-80% of dementia
  • Pathology: Aβ plaques + tau tangles
  • Risk: age, APOE ε4, modifiable (Lancet 14 factors)
  • Clinical: episodic memory → anomia → visuospatial → executive → behavioral
  • NIA-AA 2024: biological diagnosis (biomarkers)
  • Biomarkers: CSF + amyloid PET + emerging plasma (p-tau 217)
  • Symptomatic: cholinesterase inhibitors + memantine
  • DISEASE-MODIFYING: lecanemab (Leqembi, FDA 2023) + donanemab (Kisunla, FDA July 2024) — ARIA risk
  • Atypical: posterior cortical atrophy + logopenic PPA