BRICHOS-Biased Inhibition Contributes to Aβ42 Dominance in Parenchymal Plaques Despite Higher Aβ40 Abundance and Coaggregation Capability

The predominance of Aβ42 fibrils in parenchymal plaques of Alzheimer's disease (AD), despite the higher abundance of Aβ40 capable of coaggregation with Aβ42, remains an open question of the disease. We postulate that the molecular chaperone Bri2 BRICHOS, an endogenous substoichiometric inhibitor of Aβ aggregation, may contribute to this mystery. Using atomistic replica-permutation discrete molecular dynamics simulations, we investigated the modulatory effects of BRICHOS on the fibril growth of both Aβ42 and Aβ40 by comparing their self- and cross-seeding processes. Aβ42 fibrils exhibited a higher fibrillization rate and greater thermal stability than Aβ40 fibrils, consistent with their higher amyloidogenicity. Both Aβ42 and Aβ40 fibrils were capable of efficiently cross-seeding the aggregation of the other variant, with fibril growth pathways determined by the seed morphology rather than the type of incoming monomer. However, BRICHOS showed a pronounced competitive advantage over Aβ40 monomer for binding Aβ40 fibril, thereby effectively capping the growth of Aβ40. The same effect, albeit much weaker, was also observed for Aβ42 fibrillization. This differential inhibition provides a possible mechanistic explanation for the scarcity of Aβ40 in fibrillar form in the AD brain despite its greater abundance and capability for cross-aggregation. Our findings highlight the combined influence of intrinsic fibril properties and selective environmental modulators in shaping amyloid deposit composition, providing new insights into AD pathogenesis and potential therapeutic strategies.