ABSTRACT The purpose of this study is to determine the extent to which vascular risk factors are associated with biomarkers of Alzheimer’s disease (AD) risk over time in middle aged adults with heart failure with preserved ejection fraction (HFpEF). Mid-life cardiovascular risk factors contribute to the development of AD in later life and to AD progression. Pathophysiologic mechanisms in HFpEF share mechanistic pathways implicated in AD development, such as cerebral hypoperfusion, blood brain barrier (BBB) disruption, systemic and central inflammation, and neurohormonal dysregulation. These AD pathways lead to accumulation of AD biomarkers in cerebral spinal fluid (CSF) and blood. This study will enroll persons with HFpEF to elucidate vascular risk factors specific to this understudied population with pathophysiologic drivers of vascular dysfunction associated with AD risk. The proposed longitudinal study will test the hypothesis that midlife vascular risk factors predict biomarkers of AD risk in persons with HFpEF. We will test the following Specific Aims in a high-risk cohort of 80 non-Hispanic White (n=40) and Black/African American (n=40) individuals during middle age (45-65yrs) who have a diagnosis of HFpEF over 2 years: 1) assess the association of vascular risks with CSF biomarkers of AD risk over two years in middle aged adults with HFpEF, 2) assess the association of vascular risks with blood biomarkers of AD risk over two years in middle aged adults with HFpEF, and 3) assess the association of vascular risks with cognitive function over two years in middle aged adults with HFpEF. This career development award builds on previously developed strengths in studying mechanisms in cardiovascular disease pathophysiology and aims to fill the gap related to Alzheimer’s disease research in the applicant’s training. Specific career development goal included in this plan are: 1) gain expertise in the science of AD and AD biomarkers, including collecting and analyzing AD biomarkers from blood and cerebrospinal fluid and vascular function measures, 2) gain advanced training and experience in cognitive function measures, 3) gain expertise in clinical trial implementation, 4) refine knowledge in health disparities research, and 5) transition to independence and prepare for the next stage of my translational research program. Findings from this study will lead to the identification of pathways that might be amenable to interventions that improve vascular function for persons with HFpEF, with the goal of decreasing AD risk in this high morbidity population.