Modifications of the excitotoxic neurotransmitter theory of cellular damage are necessary to explain abnormalities in Alzheimer's disease. Reductions in enzymes of oxidative metabolism in Alzheimer brain and the subsequent histotoxic hypoxia may be a pathophysiological link to the neurotransmitter changes. Similar mechanisms may underlie the greater susceptibility of the aged brain to metabolic insults and this interaction may explain the age-related nature of Alzheimer's disease.