Abstract Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. We report the cryo-EM structures of Aβ42 filaments from brain. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease and Type II filaments in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from brain differ from those of filaments assembled in vitro . By contrast, in App NL-F knock-in mice, Aβ42 deposits were made of Type II filaments. Knowledge of Aβ42 filament structures from human brain may lead to the development of inhibitors of assembly and improved imaging agents.

Cryo-EM Structures of Amyloid-β 42 Filaments from Human Brain