Alzheimer's disease Study Guide

📖 Core Concepts Alzheimer disease (AD) – the most common neurodegenerative dementia (≈ 60‑70 % of cases). Typical onset – > 65 yr (early‑onset ≈ 10 % before mid‑60s). Genetic risk – APOE ε4 allele (1 copy ↑ 3‑fold risk, 2 copies ↑ ≈ 15‑fold). Familial early‑onset AD – autosomal‑dominant mutations in APP, PSEN1, PSEN2 → ↑ Aβ₄₂ production. Pathologic hallmarks – extracellular amyloid‑β plaques and intracellular neurofibrillary tangles (hyper‑phosphorylated tau). Amyloid cascade hypothesis – Aβ accumulation → downstream tau pathology, inflammation, neuronal loss. Clinical diagnosis – progressive impairment in ≥ 2 cognitive domains affecting daily function; exclusion of other causes. Biomarkers – CSF ↓ Aβ₁₋₄₂, ↑ total & phosphorylated tau; PET amyloid/tau; MRI hippocampal atrophy. Treatment – symptomatic (cholinesterase inhibitors, memantine) + emerging disease‑modifying antibodies (e.g., lecanemab). Prognosis – median survival 3‑12 yr after diagnosis; earlier onset → longer disease course. --- 📌 Must Remember APOE ε4 dose‑response: 1 allele ≈ 3× risk; 2 alleles ≈ 15× risk. Amyloid‑β length: Aβ₁₋₄₂ is the most fibrillogenic; mutations raise the Aβ₁₋₄₂/Aβ₁₋₄₀ ratio. MCI → AD: Amnestic MCI progresses to AD in > 90 % of cases. Diagnostic criteria hierarchy: NIA‑AA (2011) – research‑focused, biomarker‑driven. DSM‑5 – clinical, major/minor neurocognitive disorder. NINCDS‑ADRDA – classic clinical triad (memory loss + 1 of aphasia, apraxia, agnosia, disorientation). First‑line pharmacology: Donepezil, rivastigmine, galantamine – cholinesterase inhibitors (mild‑moderate). Memantine – NMDA antagonist (moderate‑severe). Monoclonal antibodies: lecanemab & donanemab ↓ plaque burden; modest clinical slowing; risk of ARIA. Key non‑pharm: Mediterranean/MIND diet, aerobic exercise ≥ 150 min/week, cognitive engagement, sleep 7‑8 h/night. Survival predictors: age at onset, severe cognitive/functional decline, comorbid cerebrovascular disease, malnutrition, male sex. --- 🔄 Key Processes Amyloid‑β production APP → β‑secretase (BACE1) cleavage → C‑99 fragment → γ‑secretase cleavage → Aβ₁₋₄₂/Aβ₁₋₄₀. Plaque formation Misfolded Aβ oligomerizes → fibrils → extracellular plaques → microglial activation → inflammation. Tau hyperphosphorylation Kinases (GSK‑3β, CDK5) add phosphate groups → tau detaches from microtubules → aggregates into neurofibrillary tangles. Synaptic dysfunction Soluble Aβ oligomers impair NMDA‑mediated LTP → dendritic spine loss → cognitive decline. Neurodegeneration cascade Aβ → tau pathology → oxidative stress + mitochondrial dysfunction → neuronal death → cortical atrophy (hippocampus → temporoparietal). Clinical staging Preclinical (biomarker + no symptoms) → MCI (objective deficits, preserved ADL) → Dementia (mild, moderate, severe functional loss). --- 🔍 Key Comparisons Early‑onset familial AD vs. Sporadic late‑onset AD Genetics: Autosomal‑dominant APP/PSEN1/2 mutations vs. APOE ε4 risk allele. Onset: < 65 yr vs. > 65 yr. Heritability: ≈ 90 % vs. ≈ 70 % (heritability but not familial). Cholinesterase inhibitors vs. Memantine Mechanism: ↑ acetylcholine (AChE‑I) vs. ↓ excitotoxic glutamate (NMDA antagonist). Stage: Mild‑moderate vs. moderate‑severe. Side‑effects: GI upset, bradycardia vs. dizziness, hallucinations. Amyloid‑beta hypothesis vs. Tau hypothesis Primary driver: Aβ accumulation initiates cascade vs. tau pathology may start independently. Therapeutic focus: Anti‑amyloid antibodies vs. tau‑targeted agents (still experimental). NIA‑AA (research) vs. DSM‑5 (clinical) Basis: Biomarker positivity (ATN) vs. clinical cognitive deficits + functional impact. Usage: Clinical trials vs. routine practice. --- ⚠️ Common Misunderstandings “AD is caused only by amyloid plaques.” – Plaques are necessary but not sufficient; tau pathology correlates better with clinical severity. “APOE testing predicts who will get AD.” – APOE ε4 increases risk but is not deterministic; many carriers never develop AD, many non‑carriers do. “Antidepressants cure AD because depression is a risk factor.” – Treating depression may reduce risk modestly; it does not reverse established AD pathology. “All patients benefit from monoclonal antibodies.” – Benefits are modest, limited to early disease; ARIA risk and high cost restrict universal use. “Memory loss alone equals AD.” – Must have progressive impairment in ≥ 2 domains and functional decline; other dementias can present similarly. --- 🧠 Mental Models / Intuition “The domino effect” – Aβ plaques are the first domino; they tip the cascade that knocks over tau tangles, inflammation, synapse loss, and finally cognitive decline. “Brain’s wiring vs. trash” – Tau = wiring (microtubules). When hyper‑phosphorylated, it becomes trash that clogs neuronal highways, disrupting transport. “Cognitive reserve” – Think of the brain as a library; higher education and mental activity add extra shelves, delaying when the “books” (functions) become inaccessible. --- 🚩 Exceptions & Edge Cases Early‑onset AD without known mutations – ≈ 1 % of early‑onset cases lack identifiable APP/PSEN mutations; may involve rare risk genes (ABCA7, SORL1, TREM2). APOE ε4 non‑carrier women – Still have higher incidence than men, suggesting hormonal or other sex‑specific factors. Rapidly progressive AD – Can mimic prion disease; consider atypical presentations and rule out reversible causes. Amyloid‑negative AD – Small subset with clinical AD but negative PET/CSF amyloid; may represent tau‑dominant pathology. --- 📍 When to Use Which | Situation | Preferred Diagnostic Tool | Reason | |-----------|---------------------------|--------| | Initial cognitive screen | Mini‑Mental State Examination (MMSE) or MoCA | Quick, validated, detects moderate deficits | | Distinguish AD from other dementias | Comprehensive neuropsych battery + MRI | Pattern of memory‑dominant vs. visuospatial or executive deficits | | Confirm amyloid pathology | Amyloid‑PET or CSF Aβ₁₋₄₂ | Needed for research criteria or enrollment in anti‑amyloid trials | | Assess disease stage | MRI hippocampal volume + functional ADL assessment | Structural atrophy correlates with severity | | Start symptomatic pharmacotherapy | Cholinesterase inhibitor (any) for mild‑moderate AD | First‑line, improves cognition/ADLs modestly | | Moderate‑severe disease or behavioral symptoms | Add memantine; consider low‑dose atypical antipsychotic only after non‑pharm fails | Targets glutamate toxicity; antipsychotics have high risk | | Early‑stage disease with biomarker positivity | Consider anti‑amyloid monoclonal antibody (lecanemab) if eligible | Shown to slow progression in early AD | --- 👀 Patterns to Recognize “Recent memory > Remote memory loss” – Classic early AD pattern (hippocampal involvement). “Language fluency ↓ with preserved comprehension” – Semantic fluency decline precedes aphasia. “Wandering + anosognosia” – Middle‑stage AD behavioral triad. “Ventricular enlargement + temporal lobe atrophy on MRI” – Radiologic hallmark. “CSF: low Aβ₁₋₄₂ + high p‑tau” – Biomarker signature of AD. “APOE ε4 + hypertension + sedentary lifestyle” – High‑risk cluster for prevention focus. --- 🗂️ Exam Traps Distractor: “AD is caused by tau only.” – Wrong; amyloid is considered primary driver. Distractor: “All patients with APOE ε4 develop AD.” – Incorrect; it’s a risk factor, not a certainty. Distractor: “Antipsychotics are first‑line for agitation.” – Wrong; non‑pharmacologic methods are preferred; antipsychotics are last resort. Distractor: “Memory loss alone meets DSM‑5 criteria.” – Incorrect; must have functional impairment and ≥ 2 domain deficits. Distractor: “PET‑FDG is used for early AD diagnosis.” – Misleading; FDG PET shows hypometabolism but is not recommended for early diagnosis per guidelines. Distractor: “Statins cure AD.” – No conclusive evidence; they may lower cardiovascular risk but not proven disease‑modifying. ---