Abstract Alzheimer’s’ disease (AD) affects an estimated 6.7 million people aged 65 and older in the US and the number could grow to 13.8 million by 2060. Despite major efforts to address the impacts of AD, two recently FDA approved therapies show limited clinical efficacy. Hence there is a need to identify additional therapeutic targets and facilitate discovery of biomarkers for early detection of the disease. To date, most research has focused on development of biomarkers for early detection to identify individuals at risk and for enrollment in clinical trials. Most of these biomarkers are either too expensive, not practical for routine sampling in clinical settings or not predictive of preclinical AD. Our overarching goal is to identify new biomarkers that reflect early loss of cognitive status and progression to AD through a simple blood test, and to provide potential insights into disease etiology using molecular approaches that we have successfully applied in the cardiovascular disease research field. MicroRNAs (miRNAs) are small non-protein coding RNAs that are stable in plasma and serve as potential biomarkers of AD. Moreover, miRNAs are potential therapeutic targets by virtue of their role in gene silencing at the post-transcriptional level, to prevent production of specific proteins. The proposed studies will address gaps in AD research by using untargeted and unbiased approaches to identify miRNA biomarkers to discriminate individuals with early and late-stage AD status, including individuals with mild cognitive impairment with or without amyloid deposit, a rare group of patients that receive little or no attention in research but are critical for inclusion in clinical trials. In parallel, we will use a multiomics approach, in contrast to most previous studies that have used targeted and single omic approaches, to analyze miRNA, mRNA, and protein data derived from temporal and frontal cortex brain regions from same individuals, respectively, to provide insights into potential regulatory mechanisms that participant in onset and AD progression. Our central hypothesis is that AD-related miRNAs are diagnostic biomarkers for early onset and later stages of AD development and that dysregulated miRNAs and their targets participate in AD pathophysiology, and hence could be utilized for disease attenuation. We will leverage plasma and brain samples archived at the Wake Forest Alzheimer’s Disease Research Center (WFADRC) and the University of Washington Alzheimer’s Disease Research Center (UWADRC) to test our hypothesis with the following Specific Aims: Aim 1: Identify circulating miRNA biomarkers associated with individuals at distinct stages of AD progression. Aim 2: Identify potential miRNA regulatory targets underlying early cognitive impairment and progression to AD. Overall, our study impacts are two-fold: 1) identify potential blood-based miRNA biomarkers of early cognitive dysfunction, providing avenues for early disease detection through...