The process of amyloid formation by the amyloid β peptide (Aβ), i.e., the misassembly of Aβ peptides into soluble quaternary structures and, ultimately, amyloid fibrils, appears to be at the center of Alzheimer's disease (AD) pathology. We have shown that abnormal oxidative metabolites, including cholesterol-derived aldehydes, modify Aβ and accelerate the early stages of amyloidogenesis (the formation of spherical aggregates). This process, which we have termed metabolite-initiated protein misfolding, could explain why hypercholesterolemia and inflammation are risk factors for sporadic AD. Herein, the mechanism by which cholesterol metabolites hasten Aβ 1−40 amyloidogenesis is explored, revealing a process that has at least two steps. In the first step, metabolites modify Aβ peptides by Schiff base formation. The Aβ−metabolite adducts form spherical aggregates by a downhill polymerization that does not require a nucleation step, dramatically accelerating Aβ aggregation. In agitated samples, a second step occurs in which fibrillar aggregates form, a step also accelerated by cholesterol metabolites. However, the metabolites do not affect the rate of fibril growth in seeded aggregation assays; their role appears to be in initiating amyloidogenesis by lowering the critical concentration for aggregation into the nanomolar range. Small molecules that block Schiff base formation inhibit the metabolite effect, demonstrating the importance of the covalent adduct. Metabolite-initiated amyloidogenesis offers an explanation for how Aβ aggregation could occur at physiological nanomolar concentrations.