PROJECT SUMMARY Cerebral white matter changes are common in aging adults and contribute to adverse clinical consequences. Vascular disease, specifically arterial stiffness, is thought to be the most prevalent etiology underlying white matter disease. Arterial stiffness may lead to hypoxia in downstream tissue, leaving the deep white matter tracts that lack collateral blood supply especially vulnerable. However, mounting evidence has implicated AD pathology, including amyloid-β (Aβ) and hyperphosphorylated tau (ptau), as important contributors to white matter disease. These pathologies may contribute to white matter damage in tracts overlapping with regions of Aβ and ptau deposition, such as the frontal lobe, temporal lobe, and hippocampus. Given the strong evidence suggesting vascular disease and AD pathology interact to hasten clinical progression, it is possible that these pathologies exert overlapping effects on particularly vulnerable white matter tracts, accelerating cognitive decline. The proposed research will examine age-related arterial stiffness and in vivo molecular biomarkers of AD pathology in relation to longitudinal decline in white matter microstructure (assessed on diffusion tensor imaging) over a 5-year follow-up period. Analyses will examine associations between the integrity in white matter tracts identified as especially vulnerable to each pathology and cognitive decline. The proposed research will leverage the rich resources of the Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Institute of Imaging Science, Vanderbilt Translational Clinical Cardiovascular Research Group, Vanderbilt Advanced Computing Center for Research and Education, and Vanderbilt Brain Institute. The research will be guided by an interdisciplinary mentorship team, including experts in geriatric neuropsychology, AD, cerebral small vessel disease, magnetic resonance imaging, statistical analysis, clinical management of abnormal cognitive aging, and AD molecular biomarkers. The parallel training plan will facilitate the candidate’s acquisition of the necessary knowledge and skills to study the etiologies of white matter disease in abnormal cognitive aging and propel her into a successful career as an independent physician scientist. Understanding the etiology of age-related white matter changes, especially the vulnerability of specific tracts and corresponding clinical consequences, would provide critical information regarding the neurobiology underlying cognitive decline. Findings will offer more comprehensive information regarding how white matter disease integrates into AD pathogenesis.