A Mid-to-Late Life Course Approach to Investigating the Impact of Menopause and Intervention on Brain Health

About This Grant

Project Summary Cognitive decline and neurodegenerative disorders, such as Alzheimer’s disease (AD), disproportionately affect women, who face a 48% lifetime risk of developing dementia—a nearly 40% higher risk compared to men. Heightened vulnerability in women is attributed not only to genetic and lifestyle factors but also to neurobiological shifts during midlife transitions, including menopause. Each year, 25 million women enter the menopause transition, a critical period marked by declining estrogen and neurobiological changes underlying hot flashes, sleep disruption, mood disturbances, and cognitive shifts. Despite this, sex-specific risk factors remain poorly understood, and current prediction models of AD remain predominantly sex-neutral, failing to account for reproductive history, hormonal changes, and endocrine interventions. Addressing these gaps is essential for early detection, precise risk stratification, and tailored prevention strategies for cognitive decline in women. This project seeks to uncover the neurobiological mechanisms of menopause, quantify the impact of menopausal hormone therapy (MHT) on brain health, and identify sex-specific molecular mediators of adverse brain outcomes. Using longitudinal neuroimaging, plasma proteomics, and clinical assessments, we will elucidate individual risk profiles and define actionable biomarkers for preventing late-life brain aging. We propose to (a) map neurobiological changes during menopause transition among a cohort of 120 pre- and perimenopausal women aged 40–48, an underrepresented age group in existing studies, using state-of-the-art neuroimaging, hormone, and symptom profiling. We hypothesize that perimenopausal estrogen loss leads to dysconnectivity and myelin degradation in estrogen-sensitive brain networks, correlating with symptoms (aim 1); (b) Evaluate sex-specific risk and resilience factors for adverse brain outcomes using four decades of data from the Atherosclerosis Risk in Communities (ARIC) study (N=2,649). Brain aging outcomes will be examined based on timing and formulation of MHT, testing the “critical window” hypothesis of early initiation being neuroprotective (aim 2); and (c) Identify plasma proteomic profiles mediating sex-specific risks by integrating longitudinal imaging and proteomics. We hypothesize that proteins in inflammatory and metabolic pathways link hormonal changes to adverse brain aging (aim 3). This research will yield neurobiological maps of menopause, characterize MHT's long-term impact on brain health, and identify molecular markers for precision prevention. Findings will transform clinical care by informing personalized guidelines for maintaining cognitive health in women across their lifespan.