Aggregation of amyloid-β peptides into fibrils or other self-assembled states is central to the pathogenesis of Alzheimer’s disease. Fibrils formed in vitro by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions1,2,3,4,5,6,7,8,9,10,11,12. Recent experiments1,13,14,15,16 suggest that variations in amyloid-β fibril structure in vivo may correlate with variations in Alzheimer’s disease phenotype, in analogy to distinct prion strains that are associated with different clinical and pathological phenotypes17,18,19. Here we investigate correlations between structural variation and Alzheimer’s disease phenotype using solid-state nuclear magnetic resonance (ssNMR) measurements on Aβ40 and Aβ42 fibrils prepared by seeded growth from extracts of Alzheimer’s disease brain cortex. We compared two atypical Alzheimer’s disease clinical subtypes—the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD)—with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single Aβ40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas 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 indicate that there is a qualitative difference between Aβ40 and Aβ42 aggregates in the brain tissue of patients with Alzheimer’s disease.
This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases of the US National Institutes of Health, by the UK Medical Research Council and by the National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre. We are grateful for the assistance of S. Mead, O. Avwenagha, and J. Wadsworth at the MRC Prion Unit in selection and processing of tissue samples. We thank UK neurologists for referral of rapidly progressive dementias to the NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery (NHNN), University College London Hospitals NHS Foundation Trust (UCLH). We thank the Queen Square Brain Bank for Neurological Disorders (supported by the Reta Lila Weston Trust for Medical Research, the Progressive Supranuclear Palsy [Europe] Association and the Medical Research Council) at the UCL Institute of Neurology, for provision of the human brain tissue samples. We thank all patients and their families for consent to use tissues in research.
Extended data figures
This file contains Supplementary Methods, a Supplementary Discussion and Supplementary References. The Supplementary Methods describe the selection of brain tissue samples, preparation of brain-seeded fibrils, conditions for ssNMR and TEM measurements, determination of Aβ40/Aβ42 ratios, RMSD, principal component, and crosspeak fitting calculations, statistical tests, and code availability and the Supplementary Discussion describes control experiments, chemical shift comparisons, ssNMR linewidths, and consistency among samples.