This is the third submission of an R01 requesting five years of funding to support research on vascular disease, cognition, and brain structure in individuals with atherosclerotic vascular disease (AVD) and healthy comparison participants. AVD is the leading cause of morbidity and mortality in industrialized nations and is a primary or contributing factor in well over half of all cases of dementia. Despite this, there are relatively few longitudinal studies of AVD-related cognitive decline and the factors that are most predictive of this process. The early identification of individuals who are at greatest risk for such decline will have important implications for the development of interventions aimed at preventing or attenuating this important health problem. Our research team is using an innovative physiological measure (forearm vascular function - the degree to which forearm vessels dilate in response to vasoactive agents) as an indicator of vascular health to be examined in relation to cognition and brain structure. We have published cross-sectional findings in Stroke and in Arteriosclerosis, Thrombosis, and Vascular Biology showing that this measure of vascular function is significantly related to cognition in patients with AVD, and we have obtained pilot data that suggest that this measure is also related to frontal/temporal grey and white matter volumes. The proposed research will significantly expand upon our current findings by allowing us to achieve the following goals: 1) Determine whether the relationship between vascular function and cognition is unique to AVD or is also present in the general elderly population, as part of the normal aging process; 2) Determine whether vascular function measured at baseline, and change in vascular function across time, are associated with cognitive decline across time; 3) Determine the relationships among oxidative stress-mediated suppression of vascular function, neurohumoral mediators of vasoconstriction (endothelin levels, indicators of renin-angiotensin- aldosterone system and sympathetic nervous system activation), vascular function, and cognition; 4) Determine the relationship between vascular function and specific MRI-based brain measures (both cross- sectionally and longitudinally) in patients with AVD; 5) Conduct a pilot study on vascular function and MRI- based brain measures in healthy comparison participants. We will study healthy elderly participants (N = 100) as well as those with AVD (N = 135, 85 of whom are already enrolled in our ongoing research). This will allow us to conduct baseline and three-year follow-up assessments on those participants who are newly enrolled, and six-year follow-up assessments on those who are already participating in our research. The proposed research will allow us to make significant strides toward our long-term goals of elucidating the mechanisms by which vascular disease contributes to cognitive decline, finding better ways to identify those individuals who are at greatest risk for vascular-related cognitive decline, and developing more effective treatments to prevent or attenuate this process. Atherosclerotic vascular disease is a major contributing factor to cognitive decline and dementia in the elderly. This study is designed to help clarify the mechanisms by which vascular disease causes cognitive decline and to develop better ways to identify those individuals who are at greatest risk for vascular-related cognitive changes.