Amyloid β protein (Aβ) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Aβ is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Aβ to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Aβ bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Aβ neurotoxicity suggested that Aβ neurotoxicity involves APP. Thus Aβ toxicity may be mediated by the interaction of fibrillar Aβ with neuronal membrane proteins, notably APP. An Aβ–APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.