PROJECT SUMMARY Chronic kidney disease (CKD) is a predominantly age-related disorder and is associated with accelerated cognitive function decline. Despite epidemiological evidence linking mild cognitive impairment (MCI) and dementia with kidney function decline, we still have an incomplete understanding of the factors involved in their pathogenesis suggesting that there are other unidentified age-related causal risk factors that drive the development and progression of MCI, dementia, and kidney function decline. Recent data indicates that aging humans accumulate leukemia associated somatic mutations in hematopoietic stem cells. These mutations appear to provide a competitive growth advantage to the mutant cells, allowing progressive clonal expansion which has been defined as clonal hematopoiesis (CH) and it is characterized by worsening chronic systemic inflammation. CH is associated with several pathological conditions including cardiovascular disease, however, its association with cognitive and kidney endpoints has not been explored. In addition, the underlying mechanisms driving CH remain to be determined. Hence, our primary objective is to establish an association between CH with MCI, dementia, and kidney disease progression. Given the interplay between CH and aging related changes in the bone marrow (BM) fat microenvironment, a key secondary goal of this application is to determine the role of BM fat in the evolution of CH. We will also examine blood metabolite signatures associated with higher risk for clinically meaningful cognitive and CKD endpoints and higher BM fat content. Our preliminary data demonstrated a significant occurrence of CH in patients with CKD. Also, we have shown that BM adipocytes produce a local inflammatory signature including increased interleukin-6 that promotes CH. These findings provide a strong premise for our hypothesis that CH associates with MCI, dementia and CKD, and that BM fat plays a significant role in CH development. We will leverage the unique resources of the Systolic blood Pressure Interventional Trial (SPRINT), including longitudinal data on assessment of cognitive function and CKD, biospecimens, and DNA enabling assessment of CH. In a subset of 6,000 SPRINT participants aged 50 or older with normal kidney function at baseline, we will determine CH at baseline using our targeted sequencing panel and analytic pipeline for somatic mutation calling and assess whether CH identifies those at highest risk for cognitive and kidney function impairment. We propose 3 aims; Aim 1: To evaluate the prospective associations between CH and metabolomics with incident MCI and dementia events among SPRINT participants with normal kidney function at baseline. Aim 2: To evaluate the prospective associations between CH and metabolomics with kidney disease progression events among SPRINT participants with normal kidney function at baseline. Aim 3: To define a link between BM fat and clonal hematopoiesis in CKD. Understan...