Amyloid-β peptide (AβP), long framed as a toxic byproduct of neurodegeneration, functions as a broad-spectrum antimicrobial agent — and its pathological accumulation in Alzheimer's disease (AD) may represent a dysregulated immune response to microbial invasion. This review from IIT Bombay synthesizes evidence implicating viruses (notably herpes zoster), bacteria, and fungi — via gut dysbiosis, direct CNS infection, or metabolite-driven neuroinflammation — as upstream drivers of AβP overproduction and the AD cascade.
This antimicrobial protection hypothesis, pioneered by Moir and Tanzi around 2010 and gaining traction through population-level data linking HSV-1 reactivation to dementia risk, fundamentally challenges the amyloid-cascade dogma by repositioning plaques as consequence rather than cause. The clinical stakes are significant: if microbial seeding is etiologically upstream, then decades of amyloid-clearance trials failing Phase III may reflect treating a downstream symptom. Interventions targeting gut eubiosis (prebiotics, microbiome modulation), vaccination against neurotropic herpesviruses, and judicious antimicrobial use acquire mechanistic justification here.
Critical caveats apply. This is a review, not primary data — and causality between microbial exposure and AD onset in humans remains difficult to establish given long preclinical disease windows. Most mechanistic evidence remains animal-derived or associational. Still, the orthogonal therapy framing — attacking AD indirectly through infection prevention — is strategically credible and underexplored in clinical trial design. Incremental synthesis, but potentially paradigm-reinforcing for the microbial hypothesis.
