An antisense oligonucleotide probe was used to examine the expression of gene encoding the obligatory NMDAR1 subunit of the N-methyl-D-aspartate receptor in the hippocampus and adjacent cortical areas (entorhinal and perirhinal cortices) of seven Alzheimer patients and in the same brain regions of seven control individuals. Both groups were matched according to age, sex, cause of death, post mortem delay, and tissue storage time. Densitometric analysis of in situ hybridization autoradiograms revealed a 34% (P<0.05) decrease in NMDAR1 messenger RNA levels in layer III of the entorhinal cortex in Alzheimer brains. Similar deficits. although statistically not significant, were observed in layers II and IV-VI of the entorhinal cortex, and in granule cells of the dentate gyrus. Reduced levels of NMDAR1 messenger RNA were also found in layers II-VI of the perirhinal cortex (41 53% decrease, P<0.02). There were no changes in NMDAR1 messenger RNA expression in the CA1, hilus, or subiculum. Both Alzheimer and control group show substantial intersubject variation in levels of NMDAR1 messenger RNA. The analysis of emulsion-dipped tissue revealed a trend toward a decrease in the number of silver grains overlying individual neurons in the CA1, entorhinal cortex, and granule cell layer of some Alzheimer patients. No significant relationship was detected between the levels of NMDAR1 messenger RNA and post mortem delay, tissue storage, age of the subjects, or mini mental state exam score either in control or Alzheimer individuals. In contrast, a strong inverse correlation between NMDAR1 expression and disease duration was found. These data suggest that reduction in expression of the NMDAR1 gene observed in certain regions of Alzheimer hippocampus and adjacent cortical regions is specific for the disease itself. We postulate that reduced transcript levels may reflect either regional cell loss or anomalies in glutamatergic input to the hippocampus and entorhinal cortex in Alzheimer's disease. When followed by changes at the receptor subunit protein level, altered expression of the NMDAR1 gene in Alzheimer brain may contribute, through the formation of N-methyl-D-aspartate receptors with different properties, to the previously reported modified N-methyl-D-aspartate receptor ligand binding, abnormal vulnerability of select neuronal populations to excitotoxic insult, and may also be involved in learning and memory deficits.