In the pathophysiology of Alzheimer's Disease, which form of amyloid-beta (Aβ) is currently considered most neurotoxic?
- A Aβ-40 monomers forming neuritic plaques
- B Aβ-42 soluble oligomers causing synaptic dysfunction before plaque formation ✓
- C Tau neurofibrillary tangles in the temporal lobe as the primary toxic species
- D Presenilin-1 fragments in the endoplasmic reticulum
Explanation
Current amyloid cascade hypothesis revisions identify soluble Aβ-42 oligomers (dimers, trimers, protofibrils) rather than mature insoluble plaques as the primary neurotoxic species in Alzheimer's Disease. These oligomers impair synaptic plasticity (LTP), cause mitochondrial dysfunction, trigger tau hyperphosphorylation, and activate neuroinflammation well before plaque deposition is detectable. Aβ-40 is less aggregation-prone than Aβ-42. Tau tangles (option C) are important downstream effectors of neurodegeneration but are considered secondary to amyloid pathology in the cascade model. Anti-amyloid immunotherapies (lecanemab, donanemab) target these aggregated forms and have recently shown clinical benefit in early AD.
Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.
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