Cerebral Pulsatility as a Mechanism of Accelerated Cerebrovascular Aging across the Menopause Transition

About This Grant

The menopause transition is a key period of increased cardiovascular disease (CVD) risk in women, related in part to changes in vascular health.1 Vascular mechanisms underlying CVD risk during the menopause transition may also influence women’s disproportionate risk of later-life vascular dementia2,3 and Alzheimer’s disease and related dementia (ADRD), which impacts 3x more women than men.4 Vascular health in midlife and thus, the menopause transition, is highly predictive of later-life brain health and dementia risk.5-10 It is currently unknown how vascular mechanisms of brain health change across the stages of the menopause transition.11,12 This critical gap in knowledge limits mechanism-targeted preventive interventions in midlife to reduce the burden of ADRD1,13,14 in aging women. Although cerebral blood flow is a classic and important mechanism of ADRD, our team’s promising preliminary data suggest cerebral pulsatility may be a novel candidate mechanism by which the menopause transition accelerates brain aging and ADRD risk in women. Cerebral pulsatility describes the discontinuous nature of blood flow in the fragile cerebrovasculature that is a key mechanism of cerebrovascular disease.15 Higher cerebral pulsatility16,17 may damage vascular and structural components of the brain over time16-23 and compromise brain health.18-25 Our promising preliminary data shows women i) experience linear reductions in cerebral blood flow, but a disproportionate, non-linear increase in cerebral pulsatility between 45-55 yrs of age (typical age of the menopause transition),26 and ii) are more vulnerable to cerebral pulsatility than men.27 Exaggerated increases in cerebral pulsatility across the menopause transition may contribute to accelerated brain aging in women. This idea is supported by our work identifying vascular contributors to pulsatility (large artery stiffness and characteristic impedance) that are altered in women during midlife28 and the menopause transition.29,30 Our recent meta-analysis31 indicates cerebral pulsatility is poorly characterized across the stages of the menopause transition and identified key study design components to directly address this knowledge gap. Our team is uniquely positioned to study cerebral pulsatility across stages of the menopause transition as a plausible vascular mechanism of brain aging and ADRD risk in women,11,12,31 thereby informing future intervention development. These topics align with the scientific areas of interest in sex-specific aging trajectories and mechanisms of ADRD (NOT-AG-21-050/-21-039, NOT-OD-24-079) and key foci of the White House Initiative on Women’s Health Research.