Project Summary Approximately 30% of older adults in the United States have diabetes mellitus (DM). Alzheimer’s disease and Alzheimer's disease-related dementias (AD/ADRD) are highly prevalent in this population and cognitive impairment is a major predictor for functional decline and disability in DM. Current guidelines recommend screening for cognitive impairment in older adults with DM and providing guidance for DM management. Nonetheless, no disease-modifying treatment is available and more importantly the exact mechanism underlying the link between DM and AD/ADRD is unclear. Long term hyperglycemia is known to cause brain insulin resistance and impaired neuronal insulin signaling (NIS). Impaired NIS results in neuronal cell death, neuroinflammation, amyloid β deposition and tau phosphorylation; central components of AD/ADRD pathophysiology. Given the crucial roles of NIS in brain structural integrity and cognitive function, abnormal NIS is a highly plausible, yet understudied, mechanism underlying the high risk of cognitive impairment in DM. The overarching hypothesis of this project is that abnormal NIS precedes accelerated brain structural and cognitive changes in patients with DM and modification of NIS can potentially serve as a key strategy to prevent cognitive decline in this population. NIS mediators are highly expressed in plasma enriched extracellular vesicles (exosomes) and in this study we will use this phenomenon to assess the state of NIS in each individual. We plan to leverage the existing data from the ACCORD-MIND study (a landmark multi-ethnic study that investigated the effect of glycemic control on brain structures and cognitive function in DM). We will sample 200 male and female patients with DM with various levels of glycemic control from the ACCORD-MIND study with extensive longitudinal cognitive, clinical, and neuro-imaging data (7 years of follow up). The NIS exosomes will be isolated and quantified from available fasting blood samples to investigate whether impaired NIS precedes brain volume loss and cognitive decline. We will take a stepwise analytical approach to investigate the association of NIS with the trajectories of changes in brain structure and cognitive function in our study population. We will address the dose-response impact of glycemic control, measured by changes in hemoglobin A1c (A1C), on NIS and explore the role of NIS on the association of glycemic control measures with cognitive decline and brain volume loss. Identification and characterization of NIS biomarkers related to preclinical AD/ADRD phenotypes, such as brain volume loss or cognitive decline, will offer opportunities for early interventions to slow down the pace of cognitive decline in DM. Findings of this study can inform future studies on targeted systemic glycemic control dependent on the state of NIS in order to promote brain health in patients with DM.