<p>Alzheimer’s disease is triggered by amyloid-β, with symptoms linked to synapse loss. Oligomeric amyloid-β, rather than monomeric or fibrillar amyloid-β, has been proposed to be the proximate mechanistic cause, but the relevant molecular characteristics have remained unclear. To define the biologically relevant species, we isolated a receptor-bound amyloid-β pool from Alzheimer’s disease brain by release with a receptor antagonist and purification to homogeneity. This discrete receptor-bound amyloid-β pool is ten times more abundant than free unbound amyloid-β and is comprised of 65 nm long filaments. The tips of these short filaments bind to prion protein and drive synapse loss from human neurons. Cryo-electron microscopy shows that the receptor-bound amyloid-β consists of two symmetric S-shaped amyloid-β monomers per filament rung. The overall structure is similar to much longer plaque-associated amyloid-β filaments from the same brain and fails to reveal an unrelated “oligomeric” conformation. Nonetheless, the receptor-bound amyloid-β can be distinguished from plaque filaments by the tilt angle of repeating amyloid-β subunits within each filament rung, by amino terminal conformation, by length and by amyloid seeding properties. Characterizing receptor-bound amyloid-β provides insight into neuronal dysfunction separate from plaque aggregation.</p>