Structural Variation in Amyloid-β Fibrils from Alzheimer’s Disease Clinical Subtypes

Aggregation of amyloid-β (Aβ) peptides into fibrils or other self-assembled states is central to Alzheimer’s disease (AD) pathogenesis. Fibrils formed in vitro by 40- and 42-residue Aβ peptides (Aβ40 and Aβ42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions.(1–12) Recent experiments(1,13–16) suggest that variations in Aβ fibril structure in vivo may correlate with variations in AD phenotype, in analogy to distinct prion strains that are associated with distinct clinical and pathological phenotypes.(17–19) Here we have investigated correlations between structural variation and AD phenotype using solid state nuclear magnetic resonance (ssNMR) measurements on Aβ40 and Aβ42 fibrils prepared by seeded growth from extracts of AD brain cortex. We compared two atypical AD clinical subtypes, rapidly progressive AD (r-AD) and the posterior cortical atrophy variant (PCA-AD), with typical prolonged duration AD (t-AD). Based on ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single Aβ40 fibril structure is most abundant in samples from t-AD and PCA-AD patients, while Aβ40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for Aβ42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant Aβ40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures, and suggest a qualitative difference between Aβ40 and Aβ42 aggregates in AD brain tissue.