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Oligomeric amyloid-\u00df, rather than monomeric or fibrillar amyloid-\u00df, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. Here, we define a distinct receptor-bound amyloid-\u00df pool in Alzheimer\u2019s brain by release with a receptor antagonist and purification to homogeneity. Receptor-bound amyloid-\u00df is ten times more abundant than free unbound amyloid-\u00df. The amyloid-\u00df associated with receptor is composed of 65 nm long filaments with prion protein binding at its tips. There is no evidence for an oligomeric A\u00df state interacting with human brain receptors. Cryo-electron microscopy shows two symmetric S-shaped monomers per filament rung. The tilt between rung monomers, twist along the filament axis, amino terminal conformation and amyloid seeding properties distinguish this structure from plaque-associated amyloid-\u00df filaments of the same brain. High tip:length ratio is critical for prion protein receptor interaction and synaptic damage. Characterizing receptor-bound amyloid-\u00df filament provides insight into neuronal dysfunction separate from plaque aggregation.<\/jats:p>","DOI":"10.1101\/2025.10.10.681740","type":"posted-content","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:40:28Z","timestamp":1760402428000},"source":"Crossref","is-referenced-by-count":0,"title":["Distinct Filament Conformation for Receptor-Bound Amyloid-\u00df from Alzheimer\u2019s Disease Brain"],"prefix":"10.64898","author":[{"given":"Mikhail A.","family":"Kostylev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Butan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham P.","family":"Roseman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pallavi","family":"Gopal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8188-3092","authenticated-orcid":false,"given":"Stephen M.","family":"Strittmatter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101513051102000_2025.10.10.681740v1.1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer disease","volume":"7","year":"2021","journal-title":"Nat Rev Dis Primers"},{"key":"2025101513051102000_2025.10.10.681740v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.09.001"},{"key":"2025101513051102000_2025.10.10.681740v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJ-Moa2212948"},{"key":"2025101513051102000_2025.10.10.681740v1.4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"},{"key":"2025101513051102000_2025.10.10.681740v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26071"},{"key":"2025101513051102000_2025.10.10.681740v1.6","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"2025101513051102000_2025.10.10.681740v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01249-0)"},{"key":"2025101513051102000_2025.10.10.681740v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/416535a"},{"key":"2025101513051102000_2025.10.10.681740v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3028"},{"key":"2025101513051102000_2025.10.10.681740v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm7285"},{"key":"2025101513051102000_2025.10.10.681740v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-023-01484-4"},{"key":"2025101513051102000_2025.10.10.681740v1.12","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-022-02533-1"},{"key":"2025101513051102000_2025.10.10.681740v1.13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.11.6448"},{"key":"2025101513051102000_2025.10.10.681740v1.14","doi-asserted-by":"publisher","DOI":"10.1021\/bi802046n"},{"key":"2025101513051102000_2025.10.10.681740v1.15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.643577"},{"key":"2025101513051102000_2025.10.10.681740v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.04.007"},{"key":"2025101513051102000_2025.10.10.681740v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nature07761"},{"key":"2025101513051102000_2025.10.10.681740v1.18","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.006252"},{"key":"2025101513051102000_2025.10.10.681740v1.19","doi-asserted-by":"crossref","unstructured":"Smith LM , Strittmatter SM . 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