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).
Organ Systems
nervous
Pathway Steps
APP (amyloid precursor protein) → Aβ40 + Aβ42 monomers — via β-secretase (BACE1) + γ-secretase (presenilin-1/2) sequential cleavage (amyloidogenic path). The cascade begins with sequential cleavage of APP by β- and γ-secretases, releasing amyloid-β peptides. The γ-secretase cut is imprecise, yielding a mix dominated by Aβ40 but including the more hydrophobic, aggregation-prone Aβ42. The Aβ42:Aβ40 ratio — not total Aβ — is the key determinant of disease.
Aβ42 monomers → soluble oligomers → protofibrils → fibrils → plaques — via concentration-driven aggregation; oligomers are the most synaptotoxic species. Aβ42 self-assembles through soluble oligomers and protofibrils into fibrils that deposit as extracellular plaques. The amyloid cascade hypothesis places this aggregation upstream of tau — though the weak correlation between plaque load and dementia points to soluble species, not plaques, as the toxic agents.
soluble Aβ42 oligomers → synaptic dysfunction + LTP impairment — via NMDA receptor disruption; Ca²⁺ dyshomeostasis; mitochondrial damage. Soluble Aβ42 oligomers (not the insoluble plaques) are the principal synaptotoxic species: they bind synaptic receptors, impair long-term potentiation, and drive synapse loss — the change that best correlates with cognitive decline, and the rationale for antibodies targeting oligomeric/protofibrillar Aβ.
GSK-3β / CDK5 / DYRK1A active → tau hyperphosphorylation (Thr231, Ser202, Ser396) — via kinase activity exceeds phosphatase (PP2A) capacity; insulin signaling failure contributes. In parallel, kinases including GSK-3β, CDK5, and DYRK1A become dysregulated and hyperphosphorylate tau at sites such as Thr231, Ser202, and Ser396. Hyperphosphorylation detaches tau from microtubules, both destabilizing axonal transport and freeing tau to aggregate.
hyperphosphorylated tau → paired helical filaments → neurofibrillary tangles — via tau detaches from microtubules → axonal transport failure; Braak-stage spread. Detached hyperphosphorylated tau misfolds and assembles into paired helical filaments that accumulate as intraneuronal neurofibrillary tangles. Unlike amyloid, tangle distribution tracks closely with cognitive decline (Braak staging) — the basis of tau PET imaging and tau-targeted therapeutics.
Aβ + tau + neuronal stress → microglial activation + complement-mediated synaptic pruning — via TREM2 / CR3-driven; chronic neuroinflammation accelerates loss. Aβ, tau, and neuronal stress activate microglia, which drive neuroinflammation and — via complement (C1q/C3) tagging of synapses — pathological synaptic pruning. This immune arm, highlighted by TREM2 and other risk genes, has shifted Alzheimer’s toward a neuroimmune disease model.
sustained neuronal stress → synaptic + neuronal loss → cognitive decline — via tau pathology spatially correlates with symptoms (Braak staging). Sustained synaptic dysfunction, tangle burden, and neuroinflammation culminate in synapse and neuron loss, producing progressive cognitive decline. The long preclinical phase — pathology accruing years before symptoms — is the rationale for early biomarker detection and pre-symptomatic intervention.