Structural and functional sex differences in medial temporal lobe subregions at midlife

Background: Research has increasingly recognized sex differences in aging and Alzheimer's Disease (AD) susceptibility. However, sex effects on the medial temporal lobe (MTL), a crucial region affected by aging and AD, remain poorly understood when it comes to the intricacies of morphology and functional connectivity. This study aimed to systematically analyze structural and functional connectivity among MTL subregions, which are known to exhibit documented morphological sex differences, during midlife, occurring before the putative pivotal age of cerebral decline. The study sought to explore the hypothesis that these differences in MTL subregion volumes would manifest in sex-related functional distinctions within the broader brain network.

Methods: 201 cognitively unimpaired adults were included and stratified into four groups according to age and sex (i.e., Women and Men aged 40-50 and 50-60). These participants underwent comprehensive high-resolution structural MRI as well as resting-state functional MRI (rsfMRI). Utilizing established automated segmentation, we delineated MTL subregions and assessed morphological differences through an ANOVA. Subsequently, the CONN toolbox was employed for conducting ROI-to-ROI and Fractional Amplitude of Low-Frequency Fluctuations (fALFF) analyses to investigate functional connectivity within the specific MTL subregions among these distinct groups.

Results: Significant differences in volumetric measurements were found primarily between women aged 40-50 and men of all ages, in the posterior hippocampus (pHPC) and the parahippocampal (PHC) cortex (p < 0.001), and, to a lesser extent, between women aged 50-60 and men of all ages (p < 0.05). Other distinctions were observed, but no significant differences in connectivity patterns or fALFF scores were detected between these groups.

Discussion: Despite notable sex-related morphological differences in the posterior HPC and PHC regions, women and men appear to share a common pattern of brain connectivity at midlife. Longitudinal analyses are necessary to assess if midlife morphological sex differences in the MTL produce functional changes over time and thus, their potential role in cerebral decline.

Clinical trial number: Not applicable.