Program Director/Principal Investigator (Last, First, Middle): Alzheimer's disease (AD) is the seventh leading cause of death in the United States during 2019-2020, and the most common cause of adult-onset dementia, with an increased prevalence and severity in African Americans (AA) compared to Caucasians, ranging from 14% to almost 100% higher. AD’s risk is increased by other aging- associated comorbidities including obesity and diabetes. AA have 60% higher risk of type 2 diabetes (T2DM), a condition that contributes directly to vascular disease that, in turn, may be a particularly powerful factor in the development of Alzheimer’s in AA. Significant interactions between among serum cholesterol, APOE genotype, and AD risk were found among elderly AA in prior research, and numerous studies have shown that people with T2DM have twice the incidence of sporadic AD. Insulin deficiency or insulin resistance facilitates cerebral β- amyloidogenesis in AD, accompanied by a significant elevation in APP (amyloid precursor protein). Through our ongoing translational pilot research in an AA population in the DC region, we previously identified gene expression differences as potential signatures of future AD development in persons with T2DM. Findings suggest that the amyloid beta in Amyloid Processing Pathways (APP) and Cholesterol (lipid) Biosynthesis Pathways (CBP) may contribute to the pathogenesis of AD, but we have not fully characterized all the genes in those pathways. We hypothesize that the APP and CBP pathways (gene expression alterations) in AA T2DM patients are early identifiers (biomarkers) of future progression to AD. Our interdisciplinary team of clinicians, basic scientists, epidemiologists, and biostatisticians will bring a high level of scientific rigor to the proposed supplemental project. Identifying molecular genetic features associated with AD at a preclinical stage is a future research goal that will contribute to increased accuracy in predicting and managing AD. The specific aims are as follows. Specific Aim 1 is to analyze expression patterns of specific signature genes in the APP & CBP pathways in AA participants in four groups (persons with T2DM only, with AD only, with both conditions, and with neither condition). To achieve this goal, we will use pre-configured ALZ-Profiler Arrays (qRT-PCR based profiling) in our stored biospecimens, coupled with Ingenuity Pathway Analysis (IPA). This seeks to validate the correlations revealed in our pilot studies, and to better characterize relative expression of key genes throughout these pathways. Specific Aim 2 is to validate the differentially expressed signature genes identified in Aim #1 across our patient pool. To achieve this goal, we will use the TaqMan Array to analyze stored bio-specimens from an already recruited patient pool at Howard University Hospital and validate the precise panel of genes within the particular biological pathways by integrating the clinical, epidemiologic and la...