The accumulation of amyloid-β (Aβ) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer's disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Aβ oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Aβ oligomers in vivo. Liu et al. classify brain-derived amyloid-β oligomers into type 1 and type 2. Type 2, but not type 1, oligomers have a spatiotemporal and structural relationship with amyloid plaques. Highly abundant type 2 oligomers do not impair cognition in situ, possibly due to spatial sequestration around plaques.
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The authors thank Dr. David Bennett, Rush University Medical Center, for providing human brain specimens; Dr. Sylvain Lesné and Mathew Sherman for providing aqueous extracts of human brains; and Dr. Robert Tycko for valuable advice. This work was supported by the National Institute for Neurological Diseases and Stroke (NS33249) and a gift from B. Grossman (K.H.A.), a grant from the Robert A. and Renee E. Belfer Family Foundation (J.L.J.), and the NIH intramural research program (W.Q.).