Menopause Impacts Human Brain Structure, Connectivity, Energy Metabolism, and Amyloid-beta Deposition.

Abstract All women undergo the menopause transition (MT) in their lifetime, yet little is known of how this process impacts the human brain. The MT occurs in stages characterized by unique endocrine properties that impact aging trajectories of multiple organ systems including brain. This multi-modality neuroimaging study indicates that MT stages (pre-menopause, peri-menopause, and post-menopause) are associated with substantial differences in brain structure, connectivity, and energy metabolism in regions subserving higher-order cognitive processes. Effects were specific to endocrine aging (menopause) rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions sensitive to cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer’s disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile, as well as cognitive integrity, during midlife endocrine aging of the female brain.