Public Health Issue: Alzheimer disease, a progressive brain disorder, is one of the most common causes of dementia, characterized by acquired and progressive cognitive decline, disability, and mortality. African Americans (AA) have a two-fold higher risk of developing Alzheimer disease compared to non-Hispanic whites. Alzheimer disease is a major public health concern with no effective treatment. Rationale: Changes in the levels of plasma biomarkers (amyloid β, pTau, and amyloid precursor protein, APP), have been used successfully to diagnose and monitor the onset and progression of the risk of Alzheimer disease. My current NIH grant is for a randomized, double-blind, placebo-controlled clinical trial to test the hypothesis that supplementation with vitamin D (VD) in combination with L-cysteine (LC, a GSH precursor) will optimize levels of 25(OH)VD and GSH (biological signatures) and simultaneously decrease insulin resistance in AA. We will have ongoing access to plasma and peripheral blood mononuclear cells isolated from the blood of AA enrolled in this clinical trial that can be used to measure plasma biomarkers for the risk of Alzheimer disease. Approach: AA have reduced levels of glutathione (GSH) as well as a high risk for developing Alzheimer disease. Low levels of GSH, vitamin D deficiency, and elevated oxidative stress have been linked to a higher incidence of cognitive decline in both animal and human studies. This administrative supplement presents an opportunity to examine plasma biomarkers of the risk of Alzheimer disease and the genes that regulate APP metabolism using blood collected from participants enrolled under the current NIH grant. There will be no change in the design of the clinical trial. The administrative supplement will examine the hypothesis that blood biomarkers of the risk of Alzheimer disease (functional or clinical outcomes) can be lowered beneficially by optimizing GSH and reducing levels of oxidative stress in AA subjects. Impact on Public Health: The successful completion of the additional investigations will have a significant impact on the design of future full-scale efficacy trials to investigate the potential of co-supplementation with VD+LC to reduce the inflammation/neuronal damage among AA. The development of a safe, low-cost dietary supplement that improves GSH status, and reduces the progression of Aβ deposits, would significantly improve treatment of Alzheimer disease and help to address other health disparities in the AA population. This application, which is highly responsive to NOT-AG-21-018, will not change the protocol proposed in the funded R33 application. However, it will allow analysis of additional biomarkers in the previously collected blood to examine the outcome of biological signatures associated with the onset of dementia and Alzheimer disease.