Sex-Specific Impact of Metabolic Syndrome on Brain Structures Vulnerable to Alzheimer’s Disease: A Cross-Sectional Study in a Brazilian Cohort

<b>Background:</b> Metabolic syndrome (MetS) is linked to brain degeneration and Alzheimer's disease (AD). Women, especially during menopausal transition, show increased susceptibility to AD-related brain changes. This study investigated the sex-specific neurostructural impact of MetS on brain regions vulnerable to AD. <b>Methods:</b> This cross-sectional study analyzed data from 500 participants (303 women, 197 men) from the Baependi Heart Study cohort, Brazil. High-resolution T1-weighted MRI scans were used for volumetric analysis of AD-related regions of interest (ROIs). Non-parametric quantile regression models compared ROI volumes between MetS and Non-MetS groups, stratified by sex and age (median split), adjusting for age and education. <b>Results:</b> No significant differences in ROI volume were observed between the MetS and Non-MetS groups in men. In women, findings were age-dependent. The younger cohort (≤48 years) with MetS exhibited significantly smaller left hippocampal volume (<i>p</i> = 0.02) and a trend toward smaller left middle temporal gyrus volume (<i>p</i> = 0.05) compared to Non-MetS. The older cohort (>48 years) with MetS showed a significantly larger right amygdala volume (<i>p</i> < 0.001). Furthermore, age-related volume decline in the hippocampus and middle temporal gyrus was significant in Non-MetS women but not in women with MetS, suggesting that MetS may be a confounding factor in age-related neurodegeneration. <b>Conclusions:</b> MetS is associated with sex-specific alterations in AD-vulnerable brain structures. In women, MetS may influence medial temporal lobe atrophy pre-menopause, and is linked to amygdala enlargement post-menopause. These exploratory results generate the hypothesis that MetS may uniquely predispose women to AD-related neurodegeneration, which requires critical longitudinal confirmation.