PROJECT ABSTRACT White matter (WM) microstructural and connectional alterations are increasingly recognized as sensitive biomarkers of early pathological changes in Alzheimer’s disease (AD). Due to limitations in spatial resolution and diffusion-encoding sensitivity of conventional diffusion MRI techniques, only long-range fiber tracts in deep WM have been accurately mapped and studied in AD. Little is known about the short-range association fibers (SAFs) in superficial WM, even though they contribute to 90% WM connections and are more vulnerable to age-related degeneration than deep WM according to the retrogenesis model of AD. This proposal aims to improve the accuracy and feasibility of SAF mapping using ultra-high-resolution (1 mm isotropic or higher) and high-sensitivity diffusion MRI in AD. Specifically, the candidate will develop an optimal acquisition strategy for in vivo mapping of SAFs, leveraging knowledge learned from histological validation using ex vivo diffusion MRI and polarization- sensitive optical coherence tomography; and employ developed methods to quantitatively determine when, where and how aberrant tissue properties and connections of SAFs occur in AD and how they relate to cognitive and molecular biomarkers in individuals with concurrent MRI and PET, as well as elucidate the role of short- range cortico-cortical connections in the spread of pathological tau proteins in AD. This proposal will advance next-generation diffusion MRI tractography and microstructural imaging at 1 mm isotropic or higher resolution for mapping SAFs and fine-scale structures across the whole brain in AD, clarify the effectiveness of SAFs as biomarkers of early pathological changes in AD, and shed light into the spread of tau through axonal connections. The candidate’s long-term career goal is to become an independent investigator dedicated to developing cutting-edge neuroimaging methodology, advancing the clinical utilization of these advanced neuroimaging technologies in the diagnosis, characterization and tracking of neurodegenerative diseases, and advancing understanding of the pathological mechanisms that cause dementia. This candidate has in-depth training in state-of-the-art diffusion MRI and tractography, image processing and analysis, and deep learning. During this K award, he will work with a multi-disciplinary team of mentors and collaborators to acquire additional expertise in histological validation, brain aging and neurodegenerative diseases as well as clinical translational research, which are essential for him to implement the proposed research and lead an independent laboratory. The exceptional resources, mentorship and collaboration at the Massachusetts General Hospital Martinos Center for Biomedical Imaging and Alzheimer's Disease Research Center will provide an ideal environment for the candidate to achieve both his scientific and career development goals.