T he abnormal accumulation of amyloid β-peptide (Aβ) in the form of senile (or amyloid) plaques is one of the main characteristics of Alzheimer disease (AD). Both cholesterol and Cu²⁺ have been implicated in AD pathogenesis and plaque formation. Aβ binds Cu²⁺ with very high affinity, forming a redox-active complex that catalyzes H₂O₂ production from O₂ and cholesterol. Here we show that Aβ:Cu²⁺ complexes oxidize cholesterol selectively at the C-3 hydroxyl group, catalytically producing 4-cholesten-3-one and therefore mimicking the activity of cholesterol oxidase, which is implicated in cardiovascular disease. Aβ toxicity in neuronal cultures correlated with this activity, which was inhibited by Cu²⁺ chelators including clioquinol. Cell death induced by staurosporine or H₂O₂ did not elevate 4-cholesten-3-one levels. Brain tissue from AD subjects had 98% more 4-cholesten-3-one than tissue from age-matched control subjects. We observed a similar increase in the brains of Tg2576 transgenic mice compared with nontransgenic littermates; the increase was inhibited by in vivo treatment with clioquinol, which suggests that brain Aβ accumulation elevates 4-cholesten-3-one levels in AD. Cu²⁺-mediated oxidation of cholesterol may be a pathogenic mechanism common to atherosclerosis and AD.