Receptor-bound amyloid-β in Alzheimer's disease brain exists as uniform 65 nm filaments that are ten-fold more abundant than free soluble amyloid-β, adopt two distinct atomic conformations with altered amino-terminal structure and helical twist compared to plaque-associated fibrils, and interact with prion protein receptors specifically at filament tips to mediate synaptic toxicity through a mechanism distinct from amyloid plaque pathology.

Alzheimer’s disease is triggered by amyloid-ß, with symptoms linked to synapse loss. Oligomeric amyloid-ß, rather than monomeric or fibrillar amyloid-ß, 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-ß pool in Alzheimer’s brain by release with a receptor antagonist and purification to homogeneity. Receptor-bound amyloid-ß is ten times more abundant than free unbound amyloid-ß. The amyloid-ß associated with receptor is composed of 65 nm long filaments with prion protein binding at its tips. There is no evidence for an oligomeric Aß 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-ß filaments of the same brain. High tip:length ratio is critical for prion protein receptor interaction and synaptic damage. Characterizing receptor-bound amyloid-ß filament provides insight into neuronal dysfunction separate from plaque aggregation.