Linking menopause-related factors, depression, APOE ε4, and proxies of biological aging in the UK Biobank cohort

Background: Menopause is an endocrine aging process marking the end of females’ reproductive years. In a subset of females, postmenopausal status has been linked to accelerated aging and neurological decline. A complex interplay between reproductive-related factors, mental disorders, and genetics may influence brain function and accelerate the rate of aging in the postmenopausal phase. Methods: Using multiple regressions corrected for age, we investigated the associations between menopause-related factors (i.e., menopausal status, menopause type, age at menopause, and reproductive span) and proxies of cellular aging (leukocyte telomere length, LTL) and brain aging (white and gray matter brain age gap, BAG) in 13,780 middle- and older-aged females from the UK Biobank (age range 40 – 70). We then determined how these proxies of biological aging were associated with each other, and evaluated the effects of menopause-related factors, history of depression, and APOE ε4 genotype on BAG and LTL, examining both additive and interactive relationships. Results: We found that postmenopausal status and older age at natural menopause were linked to longer LTL and lower BAG. Surgical menopause and longer natural reproductive span were also associated with longer LTL, but not BAG. BAG and LTL were not significantly associated with each other. The greatest variance in each proxy of biological aging was most consistently explained by models with the addition of both history of depression and APOE ε4 genotype. Conclusion: Overall, this study demonstrates a complex interplay between menopause-related factors, depression, APOE ε4 genotype, and proxies of brain and cellular aging, with results potentially being influenced by a disproportionate number of healthier participants among postmenopausal females. Future longitudinal studies incorporating heterogeneous samples are an essential step towards advancing female health.