Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid- (A), a 39-to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length A peptide (A1-42), the most abundant A peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human A 1-42 peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to Ϸ10-Å resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for A17-42 fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature A 1-42 fibrils is markedly different from previous cryoEM models of A1-40 fibrils. In our model, the C terminus of A forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.Alzheimer's disease ͉ iterative real-space reconstruction ͉ protein misfolding ͉ neurodegenerative disease ͉ amyloid plaques T he deposition and accumulation of amyloid is a characteristic pathology for Ͼ20 different human diseases. These diseases develop with the misfolding and aggregation of normally-soluble peptides resulting in self-aggregation and accumulation of large insoluble fibrils. One of the most common forms of dementia, Alzheimer's disease, shows typical deposition of amyloid in the form of plaques in the extracellular spaces of the brain. The principal component of these plaques is the A peptide, a 39-to 43-aa cleavage product of the amyloid precursor protein. The most abundant A peptide found in plaques is the 42-residue A 1-42 , which has a remarkable propensity to self-aggregate at high concentrations. Indeed, compared with A 1-40 , A 1-42 demonstrates much more rapid fibril formation in vitro (1-3). In addition, recent studies in animal models demonstrate that A 1-42 is exclusively required for the formation of plaques. In these mice, overexpression of A 1-42 alone resulted in the development of plaque pathology, whereas A 1-40 overexpression did not (4). Therefore, studying differences between A 1-40 and A and their aggregation products may be important in understanding pathological processes involved in fibril and plaque formation.Because of their highly insoluble but noncrystalline nature, structural determination of amyloid fibrils is refractory to traditional methods such as X-ray crystallography and solution NMR spectroscopy. Early X-ray fiber diffraction experiments revealed a generic cross- structure for nearly all amyloid fibrils, in which in-register -strands run approximately perpendicular to the fibril axis and the -sh...