Abstract The goal of this project is to determine the extent to which cardiovascular stress physiology in midlife relates to the severity of preclinical cerebrovascular disease. This goal aligns with NOT-HL-23-002 and the NHLBI Strategic Vision, which emphasize a need to understand midlife cardiovascular contributions to later life dementias. Focusing on cardiovascular stress physiology in midlife follows from cumulative evidence indicating that individuals with a phenotypic tendency to react to acute psychological stressors with relatively large rises in blood pressure (stressor-evoked blood pressure reactivity) are at risk for hypertension and adverse cardiovascular outcomes, which themselves are midlife cardiovascular risk factors for cerebrovascular disease and later life dementias. The mechanistic pathways by which stressor-evoked blood pressure reactivity may confer cerebrovascular risk are unknown. They are hypothesized in this project to include peripheral vascular remodeling and dysfunction, manifesting as arterial stiffness, endothelial dysfunction, and impaired beat-to-beat hemodynamic control. The latter are further hypothesized to promote preclinical cerebrovascular disease via a substrate for neurovascular damage; namely, cerebral pulsatility. To test predictions from these as yet unevaluated hypotheses, 3 Specific Aims are pursued in a community cohort of 538 midlife adults (aged 40-59 years; ~60% women, ~40% identifying as nonwhite; final analytic N=450 expected after attrition) who are asymptomatic for clinical cardiovascular disease and cognitive impairment. In a 2-visit protocol, volunteers will complete validated and reliable protocols to assess: behavioral, social, and biological determinants of cardiovascular and cerebrovascular health; arterial stiffness, endothelial function, and beat-to-beat hemodynamic control; cardiovascular stress reactivity; and, cerebral pulsatility and preclinical cerebrovascular disease. Aim 1 tests whether larger stressor-evoked cardiovascular (blood pressure, cardiac output, and total peripheral resistance) reactions relate to preclinical cerebrovascular disease markers (greater cerebral pulsatility, higher white matter lesion burden, decreased hippocampal volume, and increased enlargement of brain perivascular spaces) in a multivariate structural equation model. Aim 2 tests whether associations between stressor-evoked cardiovascular reactions and preclinical cerebrovascular disease markers are partly explained by arterial stiffness, endothelial dysfunction, and beat-to-beat hemodynamic control. Tertiary Aim 3 explores whether Aim 1-2 effects are moderated by known cardiovascular risks and sex as a biological variable. The proposed project seeks to characterize the extent to which cardiovascular stress reactivity in midlife is a specific cardiovascular source of risk for cerebrovascular disease. In this way, the new information from this project may identify a potentially modifiable and stress-re...