PROJECT SUMMARY Although the most significant risk factor for developing Alzheimer’s disease (AD) is advanced age, the changes in tissue microstructure that signal the shift from normal aging to AD are not well understood. Thus, in response to PAR-22-093, NOT-AG-21-039: Understanding AD in the Context of the Aging Brain, we seek to elucidate the changes in white matter microstructure in preclinical AD using advanced diffusion MRI methods developed by our group. During the 1st funding period of this grant, we established a longitudinal cohort of 165 cognitively unimpaired participants ages 45-85 who completed extensive clinical procedures (i.e. MRI, amyloid PET, neuropsychological testing, questionnaires), with an exceptional 92% retention rate at 2-year follow-up, including 14% of participants who have developed incident mild cognitive impairment (MCI) thus far. We showed that in participants with preclinical AD, late-myelinating white matter tracts demonstrate signs of myelin repair/gliosis as evidenced by greater diffusion restriction. We also observed that greater diffusion restriction in the hippocampus significantly predicts incident MCI over and above age, a finding we did not observe with other AD neuroimaging biomarkers of amyloid pathology, neurodegeneration, and white matter lesions. These results have significant implications for disease monitoring and treatment development for the very earliest stages of AD, but further work is needed to refine these methods and determine how they indicate both aging and disease progression over time. Thus, during the 2nd funding period, we seek to continue studying this cohort longitudinally every 2 years, to enhance the cohort’s inclusivity and sample size, and to add new, complementary MRI biomarkers of myelin/gliosis to test our inferences. Our overall objective is to delineate the natural history of white matter changes from normal aging to preclinical AD and to MCI/dementia, illuminating what aspects of myelin/gliosis drive changes in diffusivity, where these preferentially occur, and when in the course of disease these take place. We will continue leveraging our interdisciplinary group’s expertise in diffusion MRI (Diffusional Kurtosis Imaging, Fiber Ball Imaging) and biophysical modeling, adding new experts on T1-based myelin water imaging and 1H- Magnetic Resonance Spectroscopy to assay myelin dynamics/gliosis. We hypothesize that advanced diffusion MRI methods can indicate myelin repair/gliosis in the preclinical stage prior to myelin breakdown and axonal loss in the symptomatic stage, a trajectory that is distinct from normal, homeostatic processes such as myelin remodeling/maintenance. Thus, we aim to: Characterize longitudinal changes in white matter microstructure in aging and AD (Aim 1); Quantify microscopic axonal fiber organization in aging and AD (Aim 2); Determine the associations between diffusion MRI-derived microstructural parameters and complementary measures of myelin/gliosis in aging and AD (Aim 3). This work will have the greatest overall impact in providing the critical translational support for trials that target mechanisms such as innate immunity/inflammation and glial senescence, which are very promising yet grossly underexplored in AD especially for the asymptomatic stage.

PROJECT NARRATIVE The goal of this project is to elucidate the changes in white matter microstructure that signal the shift from healthy to pathological brain aging using advanced diffusion MRI methods. Expected outcomes from this study include clinically feasible MRI biomarkers with which to empirically test a proposed conceptual model of white matter- related changes in aging and AD, thereby providing translational support for trials of myelin/glia-focused therapies which are grossly underexplored for asymptomatic AD. Thus, this study is poised to have an impact on the evolving conceptualization of how aging leads to AD and, critically, how this can be prevented or treated.