382.4 📋 章末速蚘 Summary

382.4.1 🔑 䞀句話瞜結

Alzheimer disease (AD) = most common cause of dementia (60-80%) + leading cause of disability + death in elderly; ~ 6 million US, > 50 million worldwide; prevalence ~ 10% age 65 → > 30% age 85; women > men (longevity); pathology — amyloid-β plaques (Aβ42 oligomers most toxic) + neurofibrillary tangles (hyperphosphorylated tau) + neuronal loss + synaptic loss + gliosis + cholinergic deficit (nucleus basalis Meynert); Braak staging entorhinal/transentorhinal (preclinical) → hippocampal/limbic (MCI to early) → temporal/parietal/frontal/occipital (moderate to severe); risk factors non-modifiable — age (top) + APOE ε4 genotype (1 copy 3x risk, 2 copies 8-12x) + Down syndrome (chromosome 21 APP gene) + female sex + family history + genetic forms (APP, PSEN1 most common, PSEN2 — autosomal dominant early-onset); modifiable Lancet Commission 2024 (14 factors, up to 45% preventable) — HTN + DM + obesity + smoking + dyslipidemia + low education + head trauma + depression + hearing loss (ACHIEVE 2023 hearing aids reduce decline) + social isolation + physical inactivity + sleep disorders OSA + air pollution + excessive alcohol + vision loss (new); clinical features — early (mild) — episodic memory loss recent > remote HALLMARK + anomia (word-finding) + apraxia + agnosia + visuospatial + executive dysfunction; moderate — disorientation + ADL impairment + behavioral changes + aphasia worsens; severe — IADL/BADL dependent + mutism + bedbound + incontinence + myoclonus/seizures + cachexia; BPSD (behavioral + psychological symptoms of dementia) — agitation + aggression + hallucinations + delusions + depression + anxiety + apathy + wandering + sleep disturbance + sundowning; atypical presentations — logopenic primary progressive aphasia (AD pathology — word-finding + sentence repetition impaired) + posterior cortical atrophy (Benson syndrome — visuospatial first + reading/navigation/dressing + younger onset) + frontal AD variant (behavioral first) + Down syndrome AD; NIA-AA 2024 revised — BIOLOGICAL DIAGNOSIS based on biomarkers (Aβ + tau) rather than clinical syndrome alone — AD continuum (preclinical AD biomarker positive normal cognition + MCI due to AD + dementia due to AD); biomarkers — CSF Aβ42 ↓ + Aβ42/Aβ40 ratio ↓ + total tau ↑ + p-tau 181 + p-tau 217 ↑ + imaging amyloid PET (florbetapir, florbetaben, flutemetamol, Pittsburgh compound B) + tau PET (flortaucipir) + FDG-PET (temporoparietal hypometabolism) + MRI (hippocampal/medial temporal atrophy) + plasma biomarkers emerging — p-tau 217 most accurate + Aβ42/Aβ40 ratio + GFAP + NfL (neurodegeneration general) coming to clinical practice; MMSE 0-30 + MoCA 0-30 (more sensitive for MCI); MCI = cognitive decline beyond aging without functional impairment + amnestic MCI most likely AD + 10-15%/year progress to dementia; symptomatic treatment — cholinesterase inhibitors (donepezil/Aricept 5-23 mg/d + rivastigmine/Exelon PO or patch + galantamine/Razadyne 8-24 mg/d) for mild-moderate + memantine NMDA antagonist 5-20 mg/d for moderate-severe (can combine with ChEI) + treat CV risk factors aggressively + lifestyle + sensory aids + caregiver support; DISEASE-MODIFYING REVOLUTION 2023-2024 — lecanemab (Leqembi) FDA Jan 2023 (full Jul 2023) anti-amyloid mAb (anti-protofibril) for early AD (MCI + mild dementia) with confirmed amyloid + IV every 2 weeks + Clarity AD trial slowed cognitive decline ~ 27% CDR-SB + ARIA-E 12-13% + ARIA-H 17% (APOE ε4 homozygous highest risk) + donanemab (Kisunla) FDA July 2024 anti-amyloid (pyroglutamate Aβ) + IV monthly + TRAILBLAZER-ALZ 2 slowed decline 35% iADRS + treatment until amyloid cleared (some patients can stop); aducanumab (Aduhelm) withdrawn 2024; anti-amyloid contraindications — severe dementia + > 4 microbleeds + recent ICH + cortical superficial siderosis + major bleeding risk + active anticoagulation (relative) + APOE ε4 homozygous highest ARIA risk (consider genotyping before treatment + counseling about psychological/insurance implications); BPSD management — non-pharm first (behavioral, address pain/infection/environment/meds) + brexpiprazole (Rexulti) FDA 2023 for AD agitation + cautious atypical antipsychotics off-label BBW + citalopram (CitAD trial) + trazodone sleep + AVOID benzodiazepines (worsen); emerging — plasma p-tau 217 clinical use + GLP-1 agonists trials (semaglutide EVOKE) + lifestyle interventions (FINGER 2015, MIND-FINGERS 2024); important entities — CAA (cerebral amyloid angiopathy) often co-exists with AD (lobar hemorrhages + microbleeds + caution anticoagulation) + LATE (limbic-predominant age-related TDP-43 encephalopathy — TDP-43 in older patients with hippocampal sclerosis, mimics AD) + mixed dementia (AD + vascular very common, AD + DLB)。

382.4.2 💊 治療粟芁

  • cholinesterase inhibitors mild-moderatedonepezil (Aricept) 5 mg/d start, titrate to 10-23 mg/d + rivastigmine (Exelon) 1.5 mg BID PO or 4.6-13.3 mg/24 hr patch + galantamine (Razadyne) 8 mg/d start, titrate to 16-24 mg/d; modest cognitive benefit; GI side effects (nausea, diarrhea) + bradycardia + sleep disturbance
  • memantine NMDA antagonist moderate-severe5 mg/d start, titrate weekly to 10 mg BID (20 mg/d) + combine with ChEI; side effects dizziness, confusion
  • lecanemab (Leqembi) anti-amyloid mAb early ADIV 10 mg/kg every 2 weeks + confirmed amyloid (PET or CSF) + MRI baseline and at 5th, 7th, 14th infusions for ARIA monitoring + counsel about ARIA risk; consider APOE ε4 genotyping (homozygous highest risk)
  • donanemab (Kisunla) anti-amyloid mAb early ADIV 700 mg every 4 weeks × 3 doses, then 1400 mg every 4 weeks + treatment until amyloid clearance (PET-based) + similar ARIA monitoring
  • BPSD non-pharmacologic firstbehavioral interventions + address pain/infection/environment + caregiver education
  • AD agitation pharmacologicbrexpiprazole (Rexulti) 0.5-3 mg/d FDA 2023 + cautious atypical antipsychotics (off-label, BBW for mortality in dementia) + citalopram (limited evidence, QT concern) + trazodone for sleep + AVOID benzodiazepines (worsen cognition and falls)
  • disease-modifying lifestyleCV risk factor optimization + Mediterranean/MIND diet + aerobic exercise + cognitive engagement + social activity + sleep hygiene + treat OSA + hearing aids (ACHIEVE 2023) + treat depression
  • caregiver supportrespite care + support groups + Alzheimer Association resources + ethical/legal planning early

382.4.3 🎯 盧醫垫的考前提醒

  1. AD = most common cause of dementia (60-80%); pathology amyloid-β plaques (Aβ42 oligomers most toxic) + neurofibrillary tangles (hyperphosphorylated tau) + cholinergic deficit (nucleus basalis Meynert)
  2. Risk factors: age (top non-modifiable) + APOE ε4 (1 copy 3x, 2 copies 8-12x) + Down syndrome (APP chromosome 21) + familial (APP, PSEN1 most common, PSEN2 — autosomal dominant early-onset); modifiable (Lancet 2024: 14 factors, up to 45% preventable) — HTN + DM + obesity + smoking + low education + head trauma + depression + hearing loss + social isolation + physical inactivity + sleep + air pollution + alcohol + vision
  3. Clinical hallmark: episodic memory loss (recent > remote) insidious progressive; then anomia + visuospatial + executive + behavioral; atypical AD — posterior cortical atrophy (Benson, visuospatial first) + logopenic primary progressive aphasia + frontal AD variant + Down syndrome AD
  4. NIA-AA 2024 revised: BIOLOGICAL DIAGNOSIS based on biomarkers (Aβ + tau) — AD continuum (preclinical, MCI due to AD, dementia due to AD)
  5. Biomarkers (memorize): CSF (Aβ42 ↓ + Aβ42/40 ↓ + total tau ↑ + p-tau 181/217 ↑) + amyloid PET + tau PET + MRI (hippocampal atrophy) + plasma p-tau 217 (most accurate, emerging clinical use)
  6. Symptomatic treatment: cholinesterase inhibitors (donepezil, rivastigmine, galantamine) for mild-moderate + memantine NMDA antagonist for moderate-severe (can combine)
  7. DISEASE-MODIFYING REVOLUTION 2023-2024: lecanemab (Leqembi) FDA Jan 2023 anti-amyloid for early AD — slowed decline 27% + ARIA risk + APOE ε4 homozygous highest ARIA risk + donanemab (Kisunla) FDA July 2024 — TRAILBLAZER-ALZ 2 slowed 35% + treatment until amyloid cleared; aducanumab withdrawn 2024
  8. Anti-amyloid mAb requirements + monitoring: confirmed amyloid (PET or CSF) + MRI baseline + during treatment for ARIA-E (vasogenic edema 12-25%) + ARIA-H (microhemorrhages 17-31%); APOE ε4 homozygous highest ARIA risk — consider genotyping before treatment; contraindications include > 4 microbleeds + recent ICH + cortical superficial siderosis
  9. BPSD management: non-pharm first; brexpiprazole (Rexulti) FDA 2023 for AD agitation; cautious atypical antipsychotics (BBW); AVOID benzodiazepines (worsen); address pain, infection, environment, medications
  10. MCI vs dementia: MCI = cognitive decline beyond aging WITHOUT functional impairment; amnestic MCI most likely AD (10-15%/year progress); mixed dementia (AD + vascular) very common; CAA often co-exists with AD (lobar hemorrhages + caution anticoagulation); LATE (TDP-43 in older patients with hippocampal sclerosis) mimics AD