382.3 🏥 內科專科考前版

382.3.1 Mechanistic Deep Dive

382.3.1.1 Amyloid Cascade Hypothesis

  • APP → Aβ → oligomers → fibrils → plaques
  • Aβ42 more toxic than Aβ40
  • Triggers tau hyperphosphorylation
  • Synaptic dysfunction + neuronal death

382.3.1.2 Tau Pathology

  • Hyperphosphorylated
  • Microtubule destabilization
  • NFT formation
  • Spread along anatomical connections (prion-like)

382.3.1.3 APOE Function

  • Lipoprotein
  • ε4: less efficient Aβ clearance
  • ε2 protective

382.3.1.4 Anti-Amyloid Mechanism

  • mAbs bind Aβ → microglial clearance
  • Different Aβ species targeted by different agents:
    • Lecanemab: protofibrils
    • Donanemab: pyroglutamate (plaques)
    • Aducanumab: aggregated forms

382.3.2 Recent Trials & Updates

382.3.2.1 Lecanemab Clarity AD (NEJM 2023)

  • Slowed CDR-SB by 27%
  • ARIA-E 12.6% (mostly asymptomatic)
  • ARIA-H 17.3%
  • Death rare but reported

382.3.2.2 Donanemab TRAILBLAZER-ALZ 2 (JAMA 2023)

  • Slowed iADRS by 35%
  • CDR-SB by 22%
  • ARIA-E 24%, ARIA-H 31%
  • Treatment until amyloid clearance

382.3.2.3 NIA-AA 2024 Revision

  • Biological criteria
  • Biomarker-based staging
  • Plasma biomarkers acceptable

382.3.2.4 Plasma Biomarkers

  • p-tau 217 highly accurate
  • Coming to clinical practice
  • Less invasive than CSF/PET

382.3.2.5 Lancet Commission 2024

  • 14 modifiable risk factors
  • Up to 45% of dementia potentially preventable

382.3.2.6 ACHIEVE (2023)

  • Hearing aids reduce cognitive decline in high-risk

382.3.2.7 GLP-1 Agonists

  • Semaglutide trials (EVOKE) for AD ongoing
  • Mechanism uncertain

382.3.2.8 SHIELD-AD (2024)

  • Lifestyle intervention
  • Modest cognitive benefit

382.3.2.9 CitAD

  • Citalopram for AD agitation
  • Modest benefit
  • QT concern

382.3.3 High-Yield Specialist Points

382.3.3.1 Tx Indications Anti-Amyloid mAbs

  • Early AD (MCI or mild dementia)
  • Confirmed amyloid (PET or CSF)
  • Need MRI baseline + monitoring
  • Counseling about ARIA
  • Cost considerations

382.3.3.2 Avoid Anti-Amyloid mAbs If

  • Severe dementia

  • 4 microbleeds

  • Recent ICH
  • Cortical superficial siderosis
  • Major bleeding risk
  • Active anticoagulation (relative)

382.3.3.3 APOE ε4 Genotyping

  • Recommended before anti-amyloid treatment
  • ε4 homozygous: highest ARIA risk
  • Counseling about psychological + insurance implications

382.3.3.4 Cerebrospinal Fluid AD Profile

  • Aβ42 ↓
  • Aβ42/Aβ40 ratio ↓
  • p-tau 181 ↑
  • Total tau ↑

  • 90% sensitivity + specificity

382.3.3.5 Frontal AD Variant

  • Behavioral first (vs typical memory first)
  • Can mimic FTD
  • Memory eventually impaired
  • Amyloid PET helps distinguish

382.3.3.6 Posterior Cortical Atrophy (Benson Syndrome)

  • Visuospatial first
  • Reading, navigation, dressing
  • Posterior cortex atrophy
  • Younger onset often
  • AD pathology

382.3.3.7 Logopenic Primary Progressive Aphasia

  • Word-finding difficulty
  • Sentence repetition impaired
  • Phonological errors
  • Single-word comprehension preserved
  • AD pathology

382.3.3.8 Mixed Dementia

  • AD + vascular very common
  • AD + DLB
  • Multiple pathologies in many

382.3.3.9 Down Syndrome AD

  • Amyloid by 20s, cognitive change by 50s
  • 90% develop AD by 65
  • Behavioral changes prominent
  • Atypical presentation

382.3.3.10 Iatrogenic AD?

  • CJD transmission via dura grafts, growth hormone (historical)
  • Recent reports of Aβ deposition transmission via these — controversial

382.3.3.11 Lifestyle Trials

  • FINGER (2015)
  • MIND-FINGERS (2024)
  • Multimodal interventions

382.3.3.13 Hippocampal Sclerosis of Aging

  • Common in oldest old
  • May mimic AD

382.3.4 Pearls

  • AD 60-80% of dementia
  • Aβ plaques + tau tangles
  • APOE ε4 major risk
  • NIA-AA 2024: biological diagnosis
  • Cholinesterase inhibitors + memantine symptomatic
  • Lecanemab (Leqembi) 2023 + donanemab (Kisunla) 2024: anti-amyloid disease-modifying
  • ARIA risk with anti-amyloid (APOE ε4)
  • Plasma p-tau 217 emerging biomarker
  • Modifiable risks: HTN, DM, hearing loss, head trauma, depression, sleep, etc.
  • Atypical AD: PCA, logopenic PPA, frontal variant