The intracellular localization of glutamine synthetase (GS) in the inferior temporal cortices of non-demented elderly individuals was compared with that in brains affected by Alzheimer's disease (AD). The present study confirmed previous reports of a general decrease in GS expression in astrocytes and the expression of GS in some neurons. Several new observations were made: the morphology of astrocytes is generally unaffected by the presence of plaques, GS labeling is present in some diffuse plaques and occasional neuritic plaques, whereas the overall density of astrocytes increases 1.4-fold in AD. In addition, the present study found that the reduction in GS expression is almost entirely due to a loss of GS from perisynaptic regions of the neuropil and from the astrocytic endfeet that normally abut cortical blood vessels. These changes implicate astrocytes in glutamate excitotoxicity and ammonia neurotoxicity. It is suggested that it may be more fruitful to regard AD not as a neuronal disease, but as a disorder of astrocyte-neuron interactions. © 2001 Wiley-Liss, Inc.