Although formation of neurofibrillary tangles is a major pathological feature of Alzheimer's disease (AD), the neurotransmitter content of neurofibrillary tangle-bearing neurons has not been well characterized. We studied the hippocampus of 6 patients with pathologically verified AD and 6 control subjects using a monoclonal antibody to glutamyl-glutamate and polyclonal antisera against glutaminase and taurine. In normal hippocampus, glutamate and glutaminase stained pyramidal neurons in the cornu ammonis (CA) fields and the subiculum, as well as the dentate granule cells. Fiber staining was better seen with glutamate antisera, which in AD specimens showed reduced numbers of glutamate-immunoreactive fibers in the molecular layer of the dentate gyrus. In AD specimens, glutamate- and glutaminase-immunoreactive pyramidal neurons in the hippocampal CA fields were decreased in number and remaining neurons showed irregular shortened and disorganized dendritic fields. Taurine immunoreactivity was localized to a subset of hippocampal pyramidal neurons, which showed similar degenerative changes in AD specimens. Glutamate-, glutaminase-, and taurine-stained neurons were found to contain neurofibrillary tangles using either double immunofluorescence with tau antisera, double immunoperoxidase stains, or silver and thioflavine S counterstains. These studies show that two distinct neurochemically defined populations of pyramidal neurons in allocortex frequently show degenerative changes and develop neurofibrillary tangles in AD.