The Dual Sequestration Hypothesis as a Clinicopathological Synthesis

We propose the DSH as a unifying framework to resolve these converging crises. This clinicopathological update posits that sporadic Alzheimer’s disease, particularly in its modern manifestation, could be understood as a disease of maladaptive innate immunity. The DSH suggests reframing Aβ and tau pathologies not as intrinsic pathogens but as visible remnants of overwhelmed, evolutionarily conserved sequestration responses. The DSH does not deny that Aβ and tau can exert toxicity in excess or that alternative views regarding their primary pathogenicity have merit. Rather, it reframes their aggregation as an evolutionarily conserved containment response—one that becomes maladaptive when the brain faces an indestructible trigger for which no evolutionary precedent exists.

In this model, Aβ could be seen as an extracellular “Sarcophagus,” a first-responder mechanism that encloses pathogens or insoluble or toxic material in the interstitial space, a role supported by its antimicrobial and metal-chelating properties (Soscia et al., 2010; Atwood et al., 1998).. Tau, in turn, could function as an intracellular “Lockbox,” attempting to isolate harmful material that has been internalized. These may represent protective, containment strategies. The catastrophic shift of the Plasticene Era is the introduction of the indestructible synthetic polymer—nanoplastics—which act as permanent, non-biodegradable nucleation seeds. These seeds hijack the ancient sequestration machinery, leading to the formation of permanent, enzymatically indigestible “synthetic-protein complexes” (Gou et al., 2024).

The DSH contends that disease progression occurs via a maladaptive phase transition from stable containment to lytic failure (Ferrer, 2022). The chronic burden of these indigestible complexes leads to microglial “immune frustration,” a metabolic and inflammatory tipping point. This state could be ignited by glutamate-mediated excitotoxicity, triggering microglial NLRP3 inflammasome activation and pyroptosis—a fiery, lytic cell death (Lassmann, 2022; Wang & Shen, 2024). Pyroptosis liberates the synthetic seeds, allowing them to propagate via the brain’s glymphatic drainage system, mechanically obstructing flow and seeding pathology in a pattern that recapitulates Braak staging (Iliff et al., 2012; Rasmussen et al., 2022).

This framework offers a direct explanation for the therapeutic paradox: mAbs remove the proteinaceous sarcophagus but leave the synthetic splinter exposed, causing inflammatory rebound (ARIA) and continued seeding. It shifts the etiological focus from the host’s response to the environmental trigger and the failure of the clearance systems meant to handle it. By integrating planetary-scale environmental change with molecular neuropathology, the DSH moves the field beyond the amyloid-tau cul-de-sac, offering a new mechanistic narrative for diagnosis, therapeutic strategy, and prevention.

https://ejournals.uni-muenster.de/fnp/article/view/9368

𝐓𝐡𝐞 𝐌𝐢𝐜𝐫𝐨𝐩𝐥𝐚𝐬𝐭𝐢𝐜 𝐓𝐡𝐫𝐞𝐚𝐭 𝐀𝐜𝐜𝐞𝐥𝐞𝐫𝐚𝐭𝐢𝐧𝐠 𝐀𝐥𝐳𝐡𝐞𝐢𝐦𝐞𝐫’𝐬 𝐃𝐢𝐬𝐞𝐚𝐬𝐞

Parallel to this clinical quandary, environmental science has uncovered a novel, pervasive threat to neural integrity. Micro- and nanoplastics, ubiquitous contaminants of the Anthropocene, have infiltrated global ecosystems and, consequently, the human body. These synthetic polymer particles have been confirmed to breach critical biological barriers and have been detected in human blood, placenta, and, most critically, in cerebrospinal fluid and brain parenchyma (He et al., 2025; Lu et al., 2025;

Bhattacharyya et al., 2025; Nihart et al., 2025).

Emerging epidemiological and toxicological evidence links their presence to neuroinflammation, cerebrovascular dysfunction, and an increased risk of dementia (Wang et al., 2026; Chakrabarti, 2026; Gecegelen et al., 2025). The modern brain is therefore chronically inundated with indestructible synthetic material on a scale unprecedented in human history—a period we term the Plasticene Era.

The scale and urgency of this environmental threat have been recognized across disciplines. Thompson et al. (2024), in their retrospective marking of twenty years of microplastic pollution research, concluded that these particles now represent a “planetary boundary threat.” Microplastics pose unknown long-term biological consequences, including neurological health.

A comprehensive health impact assessment by Lamoree et al. (2025) identified the central nervous system as a critical organ of concern. Micro- and nanoplastics can cross the blood-brain barrier, trigger neuroinflammation, and potentially accelerate protein aggregation warrants urgent investigation. The Dual Sequestration Hypothesis (DSH) directly addresses these calls by proposing a specific mechanistic pathway linking plastic particulates to AD pathology.

This environmental insurgency coincides with a growing recognition in neurodegenerative disease research of the role of exogenous exposures, shifting the etiological focus toward gene-environment interactions (Crary, 2024). The convergence of these two truths—clearing hallmark proteins does not cure AD and the modern brain is saturated with a novel class of biopersistent toxicants—forms the critical context for a new synthesis.