Project 1 Summary/Abstract: Our project plan addresses critical questions regarding the pathophysiology of AD. We will investigate the relationship between reactive astrogliosis, AD pathology, cerebrovascular disease and neurodegeneration using the unique resource of a well-characterized cohort, novel radiotracers, and state- of-the-art approaches. Our planned cohort of 300 participants provides us with a unique opportunity to examine the pathophysiological mechanisms that lead to cognitive disability in the elderly. The novelty of this proposal lies in the imaging of regional reactive astrogliosis to better define the relationship of neuroimmune response to aggregation of Aβ and tau, vascular disease, neurodegeneration and cognitive decline across the AD spectrum from cognitively unimpaired to dementia. This is possible due to the recent development and validation of the first F-18 labelled MAO-B tracer to be used as a surrogate marker of reactive astrogliosis. There are very few longitudinal studies in a position to examine the long-term effects of reactive astrogliosis across the AD continuum. We will be the first to combine cross-sectional and longitudinal in vivo imaging of regional reactive astrogliosis and to examine its association with vascular disease, Aβ and tau pathology, brain structure/function, and cognition, to study the brain changes that precede the onset of the cognitive symptoms. Moreover, we will complement our neuroimaging assessments with plasma evaluations of astrogliosis (glial fibrillary acidic protein -GFAP-), AD pathology (both Aβ and p-tau-181; p-tau-231, p-tau-217-), and neurodegeneration (Neurofilament Light). A better characterization of individuals at the preclinical and prodromal stages through markers of pathology and reactive gliosis will allow accurate identification of individuals at risk of developing the disease. Our preliminary data suggests that imaging of reactive astrogliosis reveals an earlier neuroimmune response and will better inform us on the relationship to the other pathological features of AD. Using a novel PET MAO-B tracer, our team will be the first to collect and integrate this critical information. Our findings will directly translate to primary and secondary prevention strategies. The delay of clinical dementia by even as little as 18- 24 months will have a substantial societal and economic benefit to the patients, families, and society as a whole.