PROJECT SUMMARY/ABSTRACT Candidate: I am an Assistant Professor within the Department of Neurology at the Medical University of South Carolina in Charleston, SC. My career goal is to become an independent investigator within the field of Alzheimer's Disease (AD) research, with a focus on translational work aimed at improving clinical care. Currently, my main research interest is on the validity and diagnostic impact of blood plasma based biomarkers including tau phosphorylated threonine 181 (p-tau181), which has strong potential to improve the accuracy of diagnosis and disease monitoring in AD. Over the past five years, I have not been engaged in paid research activities due to a combination of circumstances including relocation to accommodate a spouse, child-rearing responsibilities, and pursuing non-research activities to facilitate earlier repayment of debt accrued during doctoral training. This re- entry supplement would facilitate a return to research activities; during the proposed funding period between August 2024 and July 2026, I would contribute to multiple peer-reviewed publications as first author, attend relevant scientific conferences, and complete additional training in relevant fields. Mentoring Team: My primary mentor will be Andreana Benitez, PhD, the Principal Investigator on the parent grant (2R01AG054159). The proposed supplement would not change the scope or activities of this grant. This is a longitudinal study examining the role of early changes in white matter microstructure in the context of preclinical AD. My interest allows for a partnership to examine the role of blood-based biomarkers in white matter within this sample. The parent grant also includes co-investigators within the Center for Biomedical Imaging (Drs. Jensen, Falangola, Brown, and Moss) and biostatistics (Dr. Nietert). This team will assist with professional development during the two-year supplement period and prepare for a career development award (K23). Research Strategy: Blood-based biomarkers such as plasma p-tau181 have emerged as an attractive and scalable model for early detection and disease monitoring in AD. However, further understanding of how this biomarker reflects AD processes is necessary, especially its relationship to white matter microstructural changes that occur in preclinical AD. This research supplement will leverage the data being collected by the parent grant to examine the role of plasma p-tau181 in preclinical AD through the following specific aims: 1) Examine the relationship between plasma p-tau181 and amyloid plaque burden in preclinical AD; 2) Analyze relationships between plasma p-tau181 and early changes in white matter diffusion restriction in preclinical AD using advanced MRI techniques; 3) Examine relationships between plasma p-tau181 and concurrent indices of cognitive functioning in preclinical AD; and 4) Determine the prognostic and longitudinal relationships between plasma p- tau181 and white matter microstructure a...