Unraveling Alzheimer’s complexity with a distinct Aβ₄₂ fibril type and specific AV-45 binding

Abnormal aggregation of amyloid-β protein (1–42) (Aβ₄₂) is the primary pathology in Alzheimer’s disease (AD). Two types of Aβ₄₂ fibrils have been identified in the insoluble fraction of diseased human brains. Here, we report that the fraction previously deemed ‘soluble’ during sarkosyl extraction of AD brains actually harbors numerous amyloid fibrils, with a looser bundling than those in the insoluble fraction. Using cryo-electron microscopy (cryo-EM), we discover a third type (type III) of Aβ₄₂ fibril that is occasionally found in the soluble but not insoluble fraction of one AD brain. We also reveal that cryo-EM structures of Aβ₄₂ fibrils complexed with the positron emission tomography tracer AV-45 show a ligand-binding channel within type I but not type III Aβ₄₂ fibrils. In this binding channel, AV-45 engages with a vertical geometry. Through the discovery of this new structural polymorph of ex vivo Aβ₄₂ fibril, our study highlights the notable structural heterogeneity of Aβ fibrils among persons with AD. (Figure presented.)