As the population continues to age, cognitive decline and dementia are becoming increasingly important public health issues. While Alzheimer's disease is the most common cause of dementia, cerebrovascular pathology contributes to at least one third of all pathologically-confirmed cases of dementia and mixed pathology accounts for at least half of all clinical dementia cases. Cerebrovascular injury is in part driven by vascular risk factors, which also contribute to cardiovascular injury and disease. Alterations in cardiovascular function may pose a risk for accelerating age-related brain injury, independent of shared vascular risk factors. Our preliminary research suggests that subclinical cardiac dysfunction is related to maladaptive brain aging, such as cognitive impairment and incident dementia, including Alzheimer's disease. Despite extensive evidence that cardiovascular changes correspond to worse cognitive outcomes, the exact mechanism of injury linking subclinical cardiovascular changes to brain changes remains unclear. One plausible mechanism is subclinical small vessel disease. We propose to leverage legacy data from an existing cohort, the Vanderbilt Memory & Aging project, to evaluate systemic blood flow, cardiac contractility, and arterial stiffening in relation to cognitive progression and neuroimaging markers of small vessel disease. Since the Vanderbilt Memory & Aging Project cohort's inception in 2012, we have completed serial (baseline, 18-month follow-up, 36-month follow-up) visits with key covariate ascertainment, neuropsychological assessment, multi-modal brain MRI, cardiac MRI, and fasting blood acquisition on older adults free of clinical stroke and dementia at enrollment. For this award, we will post-process and code new variables from raw data unrelated to previous grant aims to test our hypotheses. Results from this interdisciplinary effort will yield important insights into mechanisms underlying the association between cardiovascular function and brain changes in older adults. Such insights will provide rich information regarding subclinical factors predisposing to cognitive impairment, Alzheimer's disease, and dementia, which will contribute to future novel strategies to delay or prevent cognitive impairment and progression.

The incidence of dementia is dramatically increasing, and there is growing recognition that cardiovascular health is associated with cerebrovascular disease and cognitive impairment. Thus, there is an urgent need to identify risk factors and prevention strategies for cognitive impairment and dementia, including Alzheimer's disease. The proposed project will generate evidence to support the development of novel strategies for delaying dementia onset and progression.