Project Summary / Abstract Alzheimer’s disease (AD) and related dementia are one of the most prevalent neurodegenerative disorders in the aging population, affecting more than 1 in 10 people aged 65 and older each year in the United States alone. Since AD is a slow and complex progressive brain disease, early identification of brain changes before the onset of clinical symptoms is critical for minimizing brain tissue damage and improving the effectiveness of clinical interventions. Diffusion magnetic resonance imaging (MRI) is a promising tool for the early detection of AD because of its non-invasiveness, wide availability, and sensitivity to subtle brain microstructural changes. Unfortunately, current diffusion MRI techniques can be inadequate for several reasons, including (1) insufficient spatial resolution to accurately delineate important but fine-scale white matter pathways in the medial temporal lobe (MTL), a critical region in the early propagation of AD; and (2) a lack of specificity to reveal the underpinning brain microstructural changes from early neuronal injury and dysfunction. The innovation of this proposal mainly lies in the joint use of SNR-efficient high-resolution diffusion acquisition and advanced diffusion encoding strategies to effectively address the accuracy and specificity limitations of current diffusion MRI methods. Specifically, this project will (1) develop a high-resolution MRI protocol for more accurate segmentation of white and gray matter regions that are first affected by and play critical roles in AD propagation; (2) develop advanced diffusion encoding waveforms for more sensitive and specific characterization of subtle brain microstructural changes at the early stage of AD; and (3) use existing AD molecular biomarkers to rigorously evaluate the efficacy of the new diffusion biomarkers for early AD detection. The outcomes of this proposal will lay the foundation for studying the longitudinal AD progression, elucidating the underlying AD pathogenesis, and evaluating new intervention strategies to prevent and/or slow down AD onset and/or progression. The candidate has a strong background and extensive training in MRI physics, engineering, image processing, and brain imaging. With the additional training in cognitive neuroscience, biostatistics, and multimodal neuroimaging provided by this program, he will be well equipped as an independent researcher focusing on (1) developing advanced neuroimaging techniques with a strong focus on MRI; and (2) employing a multimodal toolset to address fundamental questions in basic neuroscience research and neurodegenerative disease studies.