The formation of fibrillar deposits of amyloid β protein (Aβ) in the brain is a pathological hallmark of Alzheimer's disease^1,2 (AD). A central question is whether Aβ plays a direct role in the neurodegenerative process in AD (refs. 3,4). The involvement of Aβ in the neurodegenerative process is suggested by the neurotoxicity of the fibrillar form of Aβ in vitro^5–11. However, mice transgenic for the Aβ precursor protein that develop amyloid deposits in the brain do not show the degree of neuronal loss or tau phosphorylation found in AD (refs. 12–16). Here we show that microinjection of plaque-equivalent concentrations of fibrillar, but not soluble, Aβ in the aged rhesus monkey cerebral cortex results in profound neuronal loss, tau phosphorylation and microglial proliferation. Fibrillar Aβ at plaque-equivalent concentrations is not toxic in the young adult rhesus brain. Aβ toxicity in vivo is also highly species-specific; toxicity is greater in aged rhesus monkeys than in aged marmoset monkeys, and is not significant in aged rats. These results suggest that Aβ neurotoxicity in vivo is a pathological response of the aging brain, which is most pronounced in higher order primates. Thus, longevity may contribute to the unique susceptibility of humans to Alzheimer's disease by rendering the brain vulnerable to Aβ neurotoxicity.