Project Summary/Abstract The Charles F. and Joanne Knight Alzheimer's Disease Research Center (Knight ADRC) at Washington University was founded as the Memory and Aging Project in 1979. Since that year, it has received continuous funding from the National Institutes of Health (NIH) and now supports an active cohort of nearly 800 participants who undergo longitudinal clinical and biomarker assessments for preclinical and symptomatic Alzheimer's disease (AD). The Knight ADRC is supported by three major NIH awards, the ADRC center grant (P50AG05681, JC Morris PI), the Healthy Aging and Senile Dementia (HASD; AG03991, JC Morris PI, Imaging Core Leader T Benzinger), and the Adult Children Study (ACS, P01 AG026276, JC Morris PI, Project 4 Leader T Benzinger). With this R01, we request funding for a new initiative which will add a novel biomarker of neuroinflammation in AD, diffusion basis spectrum imaging (DBSI) magnetic resonance imaging (MRI). Members of our research team have previously established the validity of DBSI MRI for neuroinflammation in multiple sclerosis, including both in vivo and ex vivo mouse and human studies. We now extend this research to AD, and will perform in vivo validation using positron emission tomography (PET) and ex vivo validation in human post mortem samples, including immunohistochemistry and autoradiography. Our preliminary data supports the predictive value of neuroinflammation markers in the progress from normal cognition to dementia, and in particularly, the promise of DBSI MRI for this, findings which we will validate in this larger study. We hypothesize that DBSI MRI will correspond to regional neuroinflammation in PET scans and that will correspond to areas of microglial infiltration in the autopsy specimens. We hypothesize that this relationship will be present in the earliest preclinical stages of AD, when cerebrospinal fluid (CSF) has abnormally low levels of Aβ but does not yet demonstrate abnormal levels of tau. Because DBSI MRI requires only Food and Drug Administration (FDA) approved MRI sequences, it could be rapidly extended to clinical trials or clinical populations.