In vitro, β-amyloid (Aβ) peptides form polymorphic fibrils, with molecular structures that depend on growth conditions, plus various oligomeric and protofibrillar aggregates. Detailed structural information about Aβ assemblies in the human brain has been lacking. Here, we investigate structures of brain-derived Aβ fibrils, using seeded fibril growth from brain extract and data from solid state nuclear magnetic resonance and electron microscopy. Experiments on tissue from two Alzheimer’s disease (AD) patients with distinct clinical histories indicate a single predominant 40-residue Aβ (Aβ40) fibril structure in each patient, but different structures in the two patients. A molecular structural model developed for Aβ40 fibrils from one patient reveals features that distinguish in vivo from in vitro fibrils. The data suggest that fibrils in the brain may spread from a single nucleation site, that structural variations may correlate with variations in AD, and that structure-specific amyloid imaging agents may be an important future goal.

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 experiments1,13–16 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.