White matter microstructural and macrostructural profiles during midlife reveal sex differences between men and women at different menopausal stages

Women are at greater lifetime risk for Alzheimer’s disease (AD), potentially due to midlife endocrine transition effects on bioenergetics and gray and white matter volumes. Key to effective neurotransmission is white matter integrity. In this cross-sectional diffusion-weighted imaging analysis, we investigated white matter micro- and macrostructure in 137 cognitively normal, midlife adults, including 34 premenopausal, 39 perimenopausal, 27 postmenopausal women, and 37 men. Compared to men, premenopausal and postmenopausal women exhibited greater fiber density and fiber density-cross-section (FDC) across most tracts as well as higher fractional anisotropy (FA) and lower mean diffusivity in the fornix and corpus callosum, indicating denser, more organized white matter. Perimenopausal women exhibited few differences in fiber cross-section and FDC and lower FA in the bilateral fornix, differing from what was observed in pre- and postmenopausal women. These cross-sectional results suggest menopause stage-dependent sex differences in white matter organization, coinciding with changes in estrogen availability. Importantly, the perimenopause emerges as a critical window of neural reorganization in the female midlife aging brain characterized by temporary convergence toward male-like white matter organization. Future longitudinal analyses are key to identifying women who do or do not revert to a premenopausal profile, which may inform AD risk.