Project Summary Worldwide, over 50 million people have dementia, with Alzheimer's disease (AD) accounting for as much as 70% of all cases. Recently, the NIA in conjunction with the Alzheimer's Association has proposed a biological definition of AD based on the underlying pathological processes of amyloid (A), phosphorylated tau (T), and neurodegeneration (N). Notably, blood-based biomarkers of AT(N) are now available for use in observational studies and may soon be available for clinical utilization. Unfortunately, African Americans have rarely been included in studies of AD or investigations of the AT(N) framework. This omission is critical given that they are at least twice as likely as whites to develop AD and evidence suggests that the nature of the pathology (mixed versus pure AD) and the pathways to onset may be quite different for African Americans compared to whites. The proposed research will use use the Family and Community Health Study (FACHS), a unique 25-year ongoing study of physical and psychosocial well-being among several hundred African American families, to investigate the extent to which a variety of social and economic stressors, lifestyle and genetic factors, rate of aging, and chronic illness impact trajectories of AT(N) biomarkers. The few extant African American dementia studies use samples with higher income and education than the general African American population. In contrast, the FACHS sample contains a substantial proportion of individuals who have faced the challenges of economic hardship, low education, and discrimination for most of their lives. Our team of investigators from the University of Georgia and the Mayo Clinic will begin by performing assays of AT(N) biomarkers using frozen blood samples drawn in 2008 and 2019, as well as a new round of blood samples to be obtained in 2024. These data will enable us to use growth curves with individually varying time points (age) to estimate developmental trajectories of AT(N) biomarkers. Next, we will investigate the unique contributions of various environmental, lifestyle, and biological/physiological factors in accelerating these AT(N) trajectories. We are especially interested in testing models where biological/physiological markers of health serve to mediate or moderate the effect of lifestyle and environmental circumstances on changes in AT(N) biomarkers. Finally, Covid-19 data is currently being collected from the study sample and will be available for use in the proposed project. Thus, we will be able to examine whether AT(N) biomarkers at waves 5 and 8 increase the chances of contracting Covid-19, as well as if having suffered a severe case of the illness elevates AT(N) markers at wave 9.