AbstractBackgroundTwo‐thirds of all persons with late‐onset Alzheimer’s disease (AD) are female. The transition to menopause, or perimenopause, negatively impacts the female brain and is proposed to contribute to a female’s greater lifetime risk for dementia. Declining 17‐β estradiol levels during perimenopause is associated with markers of AD pathology, such as reduced cerebral glucose metabolism. Preliminary evidence suggests APOE4‐positive perimenopausal females have greater amyloid In cognitively normal individuals, the T1‐weighted and T2‐weighted (T1w/T2w) ratio from magnetic resonance imaging can be used as a non‐invasive proxy measure of amyloid‐β deposition. Specifically, higher T1w/T2w ratios are associated with higher amyloid‐β accumulation in cognitively normal individuals. Thus, to better understand the impact of perimenopause on the female brain and cognitive health, we compared the T1w/T2w ratio, hippocampal volume, and cognitive performance in perimenopausal females vs. aged‐matched males.MethodsData was acquired from the Human Connectome Project. We included 44 perimenopausal females, defined by the Stages of Reproductive Aging Workshop + 10 Staging System, and 44 age‐matched males. Executive function was measured by the Flanker Task in the NIH Toolbox Cognition Battery and data were available for all 88 individuals. Hippocampal volume data were available for 23/44 perimenopausal females and 27/44 age‐matched males. T1w/T2w neuroimaging data were available for 19/44 perimenopausal females and 27/44 age‐matched males. Between‐group differences in these measures of interest were determined by analysis of covariance (ANCOVA). For the Flanker Task ANCOVA model, the Montreal Cognitive Assessment score and free estrogen levels were included as covariates. For hippocampal volume model, intracranial volume was included as a covariate. For the T1w/T2w ratio model, the Pittsburgh Sleep Quality Inventory score was included as a covariate.ResultsPerimenopausal females performed significantly worse vs. their male counterparts on the Flanker Test (mean difference: ‐28.194; p = .000). Compared with age‐matched males, perimenopausal females had a significantly smaller hippocampal volume (mean difference: ‐544.829; p = .033) and higher T1w/T2w (mean difference: 0.290; p = .042).ConclusionOur results support the hypothesis that the menopause transition is a critical window to intervene to reduce the risk of cognitive impairment in females.