Excessive activation of N-methyl D-aspartate (NMDA) receptors by endogenous glutamate (Glu) causes excitotoxic neuronal degeneration in acute central nervous system injury syndromes such as stroke and trauma. Early attempts to link NMDA receptor hyperactivity (NRHyper) to Alzheimer disease (AD) were stymied by evidence in 3 separate species (mice, rats, and monkeys) that, with advancing age, the NMDA receptor system becomes markedly hypoactive. While this would seem to argue against a role for NMDA receptors in AD, we have recently found in animal studies that, when the NMDA receptor system is rendered markedly hypoactive, a disinhibition syndrome is triggered in which low-grade chronic excitotoxic activity (fueled by acetylcholine and Glu) is unleashed that can cause a widespread pattern of neuronal degeneration resembling that seen in AD. Therefore, we postulate that NMDA receptor hypoactivity (NRHypo) associated with advancing age may have an important contributory role in AD and that the main difference between the aging AD brain and the aging "normal" brain is that a heavier burden of certain adjunctive risk factors may be present in the AD brain that promote the NRHypo state and increase the likelihood that widespread neurodegeneration will occur.