ABSTRACT This project will explore how alterations in neuroimmune interactions, neurovascular signaling, and cerebral metabolism contribute to Alzheimer's disease (AD) pathology, along with the potential benefits of exercise (aka physical activity). Given the rapid, aggressive deterioration in cognition and function following clinical prognosis and the dire threat that AD poses to the rising aging population, the current lack of therapeutic techniques and early, robust diagnostic markers of AD onset and progression constitutes a critical challenge for modern healthcare. In addition to strongly associated pathological hallmarks such as accumulation of amyloid-β oligomers/plaques and neurofibrillary tangles, AD progression involves a pronounced neuroinflammatory response from CNS cells like microglia and astrocytes, as well as impairments to cerebral blood flow, energy metabolism, and cellular signaling. These processes reportedly initiate several years before the first symptoms of cognitive decline become evident. Because no individual preclinical AD symptom correlates perfectly with cognitive impairment, untangling the relationships and interdependencies between these pathological alterations is necessary to better understand the complex pathogenesis of AD, and it requires characterization of intricate cellular and vascular interactions with high spatial resolution in living brains of preclinical models. Furthermore, although the protective mechanisms remain unclear, physical activity shows promise for reducing the likelihood and severity of cognitive impairment in elderly subjects. Using a broad assortment of custom-designed advanced microscopy methods, we will explore, at the cellular and microvascular level, how seemingly distinct neuroimmune and cerebrovascular changes are interrelated and how they collectively contribute to the devastating AD-related neurodegeneration in preclinical mouse models of AD. We will also investigate how physical activity can mitigate these neuroimmune and neurovascular alterations. The results will help us understand in much greater detail the multifaceted structural and functional changes that ensue in the brain over the ~2 decades before clinically-observable cognitive deficiencies manifest, and they will help guide new early intervention and treatment strategies to minimize AD-related cognitive degradation.