Sex-Divergent Patterns in Hippocampal and Cortical NMDA Receptor Density Across the Alzheimer’s Disease Continuum

While the loss of NMDA receptors (NMDARs) is associated with Alzheimer’s disease (AD) severity, the effect of sex or the relationship between regional NMDAR density and antemortem cognitive status across the AD spectrum has not been examined. We performed quantitative in vitro autoradiography of the hippocampus, entorhinal cortex (EC), and parietal cortex using NMDAR and tau radioligands. Relationships between regional NMDAR density and cognitive status assessed by the Mini Mental State Examination (MMSE), and between NMDAR and tau density, were examined by bivariate correlations. In both sexes, the largest AD-related decreases in NMDAR density were observed in the cornu ammonis 1 (CA1) field. However, there was a significant diagnosis by sex interaction driven by sex-specific differences in the mild cognitive impairment (MCI) stage, with lower NMDAR density in MCI women, but not MCI men relative to same-sex controls. Within diagnosis analyses revealed positive correlations between NMDAR density and MMSE scores and significant negative correlations between EC NMDAR and tau density, which was significant only in AD men. Our data show that differences in hippocampal NMDAR density across the AD continuum are modulated by sex and may contribute to the known sex differences in the clinical trajectory of the disease.