PROJECT SUMMARY/ABSTRACT Alzheimer’s disease and Alzheimer’s disease-related dementia (AD/ADRD) incidence is high in older adults with stroke. There is a fundamental gap in understanding how vascular risk factors (VRFs) influence risk of post-stroke AD/ADRD. Poor understanding of the biological factors driving post-stroke AD/ADRD risk is a critical barrier to the design of interventions aimed to protect the brain health of stroke survivors. The long-term goal is to develop, test, and disseminate VRF interventions that reduce post-stroke AD/ADRD for diverse populations. The study objective is to quantify how VRFs influence post-stroke AD/ADRD risk to inform preventive interventions tailored to stroke survivors and inform clinical care and policies. Post-stroke AD/ADRD is an excellent model of a serious, chronic illness of aging with high prevalence and costs. High blood pressure (BP), diabetes, and high cholesterol are ideal biological VRFs because they are common and modifiable with a wide range of effective therapies for management. Our central hypothesis is that post-stroke VRF levels contribute to post-stroke AD/ADRD. The rationale for the proposed research is that knowing the impact of VRF levels and stroke (sub)type on post-stroke AD/ADRD will improve our understanding of vascular biology and translate into new and innovative approaches for prevention of post-stroke AD/ADRD. Guided by strong preliminary data, this hypothesis will be tested through 3 specific aims: 1) Quantify the influence of post-stroke VRF levels on post-stroke cognitive trajectories and AD/ADRD, and explore how sex and race affect these relationships; 2) Clarify the relationships between stroke subtype and post-stroke cognitive trajectories and AD/ADRD, and explore how VRFs, sex, and race affect these relationships; and 3) Refine and expand an existing AD/ADRD-CVD computer simulation model by adding post-stroke AD/ADRD and results from Aims 1 and 2 to quantify the subset of stroke events, sample size, and duration of trials that are adequately powered to find clinically important and plausible effect sizes of VRF lowering on post-stroke AD/ADRD. The results of Aims 1 and 2 will be the identification of both VRF targets for interventions to reduce post-stroke AD/ADRD risk and the sub-groups of stroke survivors most likely to benefit from VRF lowering. The results of Aim 3 will be a new simulation model applicable to stroke survivors that can be used to inform clinical research trials, clinical care, and policies. This research is innovative because it will ultimately yield a novel simulation model that could provide new guidance that may change clinical practice and health policy for stroke survivors. The proposed study is significant because it will generate new knowledge and methods to understand the impact of optimal VRF treatment intensity on post-stroke AD/ADRD risk and improve the design of VRF lowering trials in stroke survivors. Ultimately, such knowledge has the potential to inform the development of targeted interventions to improve the prevention of post-stroke AD/ADRD and to reduce AD/ADRD-related disability in older Americans.

NARRATIVE The proposed research is relevant to public health because the discovery of the biological mechanisms contributing to post-stroke cognitive decline and Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) is ultimately expected to lead to new vascular interventions that protect the cognitive health of Americans. The proposed research is relevant to the part of NIH’s mission of developing fundamental knowledge that will help enhance the health of older adults and reduce the burdens of human disability.