Category: disease_cascade
The dominant pathogenic model for Alzheimer disease (AD), articulated by Hardy & Selkoe (1992) and updated through 2025+. Step 1: APP (amyloid precursor protein) processing — α-secretase cleavage is non-amyloidogenic; β-secretase (BACE1) + γ-secretase (presenilin-1/2 complex) cleavage produces Aβ40 + Aβ42 monomers. Step 2: Aβ42 aggregation kinetics — oligomers (soluble, synaptotoxic) → protofibrils → mature fibrils → plaques. Soluble oligomers are the most toxic species; plaques may be a less-toxic sink. Step 3: tau hyperphosphorylation — GSK-3β + CDK5 + DYRK1A phosphorylate tau at AD-specific epitopes (Thr231, Ser202/Thr205, Ser396/404) → tau detaches from microtubules → forms paired helical filaments → neurofibrillary tangles (NFTs). Tau pathology spatially follows Braak staging (entorhinal → hippocampus → neocortex) and correlates better with cognitive decline than Aβ. Step 4: synaptic + neuronal loss — Aβ oligomers disrupt LTP, NMDA receptor function, glutamate excitotoxicity; tau disrupts axonal transport. Step 5: neuroinflammation — Aβ activates microglia + complement → TREM2 + CR3-mediated synaptic pruning (cross-link [[neuroinflammation_microglia_priming]]); chronic neuroinflammation accelerates neurodegeneration. Genetics: familial AD (PSEN1, PSEN2, APP mutations) — early-onset; APOE-ε4 — late-onset risk factor (5-15x); TREM2, SORL1, ABCA7 — modest-effect GWAS hits. Therapeutics: cholinesterase inhibitors (donepezil, rivastigmine, galantamine) — symptomatic, modest effect; memantine — NMDA modulation; anti-amyloid mAbs (aducanumab, lecanemab, donanemab — not yet in registry) — first disease-modifying class but ARIA-E/H side effects, modest clinical benefit; psychedelic + ketamine programs in early trials. Cross-links: [[bdnf_trkb_neurotrophic]] (chronic anti-AD axis), [[neuroinflammation_microglia_priming]], [[mtor_signaling]] (rapamycin neuroprotection signal), [[apoptosis_bcl2_axis]], [[ros_oxidative_stress]] (oxidative + lipid peroxidation co-injuries).