Project 2: Project Summary/Abstract Brain amyloidosis is necessary but insufficient for the development of symptomatic Alzheimer disease (AD). Whether and when an individual with brain amyloidosis develops symptomatic AD likely depends on a myriad of additional biological, demographic, social and environmental factors. Besides brain amyloidosis, many other pathophysiological processes are involved in AD and could potentially affect development of symptomatic AD, including tauopathy, synaptic dysfunction, neuronal injury/death, astrocytosis/microgliosis and inflammation. Demographic factors including race and social determinants of health (SDOH), including discrimination and adversity, adverse early-life experiences, current stress and social support, and neighborhood level disadvantages, could also play a role in modifying symptom onset. In this study, plasma and cerebrospinal fluid (CSF) biomarkers that represent diverse aspects of AD pathophysiology will be measured and used to predict the onset of symptomatic AD. The effects of demographic factors and SDOH will be examined to identify factors that modify expression of symptomatic AD and may underlie the disparities in AD prevalence in certain populations, such as African Americans. Fluid biomarkers will be used to examine the potential mechanisms by which demographic factors and SDOH exert their influence on symptomatic AD. Whether demographic factors and SDOH affect the pathological progression of AD will also be explored. Additionally, to better understand the complex role of inflammation in AD, high throughput proteomic data have been analyzed to identify plasma and CSF proteins related to inflammation that change in asymptomatic brain amyloidosis and symptomatic AD. Because these candidate biomarkers of inflammation have different biological functions compared to the biomarkers currently studied in our cohort, one or more candidate biomarkers may provide novel insights into AD biology and potentially improve AD diagnostics. Further, all fluid biomarkers will be compared with imaging measures of inflammation and tauopathy (Project 1), the gut microbiome and gut function (Project 3), and physical activity and cardiovascular risk factors (Project 4). These analyses will better characterize the fluid biomarkers and may indicate the pathophysiological processes that are modified by the gut microbiome and gut function, physical activity, and cardiovascular risk factors. Overall, this Project will use fluid biomarkers to better understand the complex biological, demographic, social and environmental factors that mediate the relationship between brain amyloidosis and symptomatic AD.