Alzheimer's disease in the era: a clinicopathological update on the dual sequestration of amyloid and tau as hijacked innate immune responses.

The defining neuropathological hallmarks of Alzheimer's disease (AD)-amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs)-are now understood to exist along a continuum with brain aging, yet their fundamental trigger in sporadic disease remains enigmatic. The clinical failure of therapies targeting these proteins, despite their successful removal, underscores a critical dissociation between hallmark pathology and core pathogenesis. This clinicopathological update synthesizes emerging evidence on pervasive environmental nanoplastics (NPs) with the persistent paradoxes of AD to propose the dual sequestration hypothesis (DSH). We suggest that Aβ plaques and tau NFTs could be reinterpreted as evolutionarily conserved, compartment-specific innate immune sequestration mechanisms-an extracellular "sarcophagus" and an intracellular "lockbox"-based on their roles in microbial defense and stress response. We posit that in the modern era, indestructible NPs detected in human cerebrospinal fluid (CSF) and brain tissue act as permanent, inorganic nucleation seeds that hijack these responses, forming indigestible synthetic protein complexes. NPs directly nucleate Aβ fibrillation and tau hyperphosphorylation, initiating the sequestration response. Chronic microglial engagement with these complexes triggers a state of "immune frustration," leading to a maladaptive phase transition. This pivot could be explained by glutamate excitotoxicity, which drives microglial NLRP3 inflammasome activation and pyroptotic cell death. Lytic pyroptosis liberates intact synthetic seeds into the paravascular space, where they are distributed via glymphatic flow, physically obstructing clearance and providing a mechanistic model for the stereotypical progression of Braak stages. The DSH offers a unified explanation for the therapeutic failure of anti-Aβ/anti-tau antibodies (which remove the biological response but not the synthetic trigger) and amyloid-related imaging abnormalities (ARIA) as an inflammatory rebound. It necessitates a paradigm shift in neuropathological practice, calling for novel detection techniques to visualize the synthetic core within classical lesions, thereby unifying environmental etiology with canonical pathology. The presence of synthetic NPs at the physical center of Aβ plaques and tau tangles in human AD brain tissue is currently a prediction of the DSH awaiting empirical validation, not an established finding.