The Role of Reproductive Aging for Racial Differences in AD/ADRD from Midlife to Older Age

PROJECT SUMMARY The prevalence of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) is predicted to nearly triple to 152.8 million cases worldwide by 2050. Women have double the risk versus men, and as early as midlife, Black individuals have nearly double the risk versus White individuals. For women, the midlife (~40-60 yrs.) is characterized by the menopausal transition, accompanied by the loss of potentially neuro- protective and cardio-protective sex hormones. Earlier menopause means earlier exposure to decreased sex hormones and may increase AD/ADRD risk. Further, reproductive surgeries (hysterectomy and/or bilateral oophorectomy) can prematurely induce menopause, resulting in the sudden and often complete loss of hormones, and may be a modifiable risk factor for AD/ADRD. Data suggest that Black women have earlier menopause than White women – approximately 1 year for natural and up to 10 years earlier for surgical menopause. Historical and existing racial bias may contribute to higher prevalence and timing of surgical menopause in Black women. The few studies of menopause and long-term AD/ADRD risk are limited due to potential bias in the measurement of menopausal age/type, bias due to selection into later life studies, particularly affecting Black women, and little data to assess relations to disparities. The proposed project will comprehensively assess the contribution of early menopause to overall risk and Black-White disparities in AD/ADRD diagnoses (K99) and development (R00) by harmonizing data from 25,051 women (30% Black) in 3 cohorts: Study of Women’s Health Across the Nation (SWAN, menopausal transition to 75+ yrs.), Women’s Health Initiative (post-menopause to 80+ yrs.) and Cardiovascular Health Study (65+ yrs.). Harmonizing cohorts with adequate sample size to gauge disparities and “gold-standard” measurements of menopause (SWAN) and AD/ADRD (adjudicated diagnoses, neurocognitive tests over time, and neuroimaging markers of AD/ADRD) while applying methods that I previously developed to account for selection bias, will address prior limitations. This proposal will ensure I get the training I need as a lifecourse social epidemiologist to work independently with AD/ADRD data, to further address bias limitations in lifecourse data, and to estimate causal impacts on disparities. Through the K99/R00 award, I will leverage the expertise of my mentors and my prior training in single cohort longitudinal methods and lifecourse disparities to gain additional training in 1) AD/ADRD diagnoses and development, 2) multi-cohort harmonization/pooling, and 3) causal intervention modeling. Completion of this proposal will result in scientific presentations, publications, and preliminary data to successfully compete for R01 funding that examines cardio-metabolic mediators of reproductive aging and AD/ADRD disparities. Results will elucidate unique midlife targets for prevention in women; supporting a potential paradigm shift for gerontologists and clinicians, explicating the importance of maintenance of reproductive organs and reproductive aging’s role in women’s, especially Black women’s, long-term health.