The various ligand binding sites of the N-methyl-D-aspartate receptor complex in the hippocampal formation and parahippocampal gyrus of Alzheimer's disease patients and age-matched normal individuals were examined using quantitative autoradiography. The hippocampus and parahippocampal gyrus of the normal elderly brain exhibited virtually identical distributions of L-[3H]glutamate, [3H]5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-iminemaleate ([3H]MK-801), [3H][(+/-)2-carboxypiperazine-4-yl]propyl-1-phosphonic acid ([3H]CPP) and strychnine-insensitive [3H]glycine binding sites (r greater than 0.87) suggesting that binding occurred to different domains of the same receptor macromolecule. The binding of [3H]MK-801 to channel-associated phencyclidine sites appeared to be most severely impaired in Alzheimer's disease, especially at the anterior hippocampal level. When the data were averaged and the means for Alzheimer's disease and control group compared, a 34% decrease (P less than 0.01) in [3H]MK-801 binding was identified in the CA1 stratum pyramidale and a smaller decrease was found in the dentate gyrus molecular layer, parahippocampal gyrus and subiculum. The CA1 region exhibited a similar 35% reduction (P less than 0.05) in L-[3H]glutamate binding to N-methyl-D-aspartate-sensitive sites. This decrease most probably reflected a decline in receptor density. Binding of [3H]CPP to antagonist-preferring sites and [3H]glycine to glycine modulatory sites did not change significantly. However, a marked intersubject variability in N-methyl-D-aspartate receptor binding was observed in control and Alzheimer's disease groups. This variability was not related to age, sex or post mortem delay. Some Alzheimer's disease patients showed markedly reduced receptor binding levels, while others showed no changes or even increased binding. The loss of N-methyl-D-aspartate-sensitive sites did not correlate with a loss of neurons in the CA1 region (r = 0.286). Similarly, no correlation between the level of binding to N-methyl-D-aspartate-sensitive sites and the density of neuritic plaques and neurofibrillary tangles was found. Intersubject variability in N-methyl-D-aspartate receptor responses in the Alzheimer's disease group may partially explain conflicting reports in the literature on the N-methyl-D-aspartate receptor changes in Alzheimer's disease, and imply that caution should be exercised before making any generalizations about receptor changes in Alzheimer's disease based on mean values only. The analysis of the individual Alzheimer's disease cases may also be valuable in determining the mechanism(s) underlying the disease.