Mid-Career Program for Vascular Contributions to Alzheimer's disease

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The goal of this K24 revised application is to build and enhance a research and training program focusing on investigating mechanisms and potentially related therapies for vascular contributors to cognitive aging and Alzheimer’s disease (AD). The scientific basis for focusing on this area of Patient-Oriented Research (POR) is that increasingly, alterations in both systemic and brain vascular systems are being identified as risk factors and potentially involved in the causal pathway for both age-related cognitive decline and dementia, including AD. Cardiovascular disease (CVD) and Alzheimer’s disease (AD) share many risk factors, such as hypertension and diabetes. A common potentially unifying hypothesis is that both CVD and AD involve an endothelial dysfunctional state that affects multiple brain processes such as perfusion, hemodynamic regulation, blood-brain barrier permeability, atherosclerotic progression and immune-inflammatory pathways leading to cognitive decline and AD pathology. From a therapeutic perspective, angiotensin receptor blockers (ARB) have a pleiotropic effect on the endothelium and my studies conducted over the last few years suggest it has a therapeutic potential. My career aims under this application is to (a) establish a POR training program focused on clinical trials into my current and future funded research activities; (b) Identify and train clinician and non-clinician investigators, particularly from underrepresented minorities, interested in being engaged in POR; and (c) enhance my research skills- through learning new proteomic methods and cell biology for development of biomarkers in AD clinical trials, and mentorship skills in POR. To achieve these career goals, I will leverage an excellent research and training environment at Emory University and build on a robust ongoing and NIH-funded set of studies (1 cohort and 2 active clinical trials) to experientially learn and teach these new skills. Specifically, I propose ancillary studies to my active research that aim to: (d) validate endothelial-based proteins discovered in untargeted proteomics in the CSF collected from individuals in my ongoing 3 studies and investigate if they are altered after 1 year of angiotensin receptor blocker treatment; and (e) to investigate the effect of ARBs on progenitor cells, linked to AD, and perform a pilot study to assess if using scRNAseq on peripheral blood (with and without pharmacological bone marrow mobilization) reveals differential functions of these cells. The success in mentoring clinicians and scientists in POR to date and the robust and productive research activities ensures my success. This K24 is a critical step in my midcareer to ultimately reach my leadership and independence goals.