PROJECT SUMMARY/ABSTRACT Type 2 diabetes increases a person’s risk for cognitive impairment syndromes including, cognitive decline, mild cognitive impairment, and Alzheimer’s Disease and its related dementias. However, our ability to identify who among people living with type 2 diabetes is most likely to develop a cognitive impairment syndrome is limited because we have an incomplete understanding of the molecular mechanisms that lead to cognitive issues in people with type 2 diabetes. A better understanding of these molecular mechanisms can help to identify biomarkers that predict risk for cognitive impairment syndromes. Proteomic analyses provide an efficient and comprehensive approach to identifying molecular mechanisms of disease and are also recognized as an effective platform for biomarker discovery. However, to date, few human studies have applied proteomic approaches to investigate the mechanisms that drive development of cognitive impairment syndromes in people living with type 2 diabetes. Thus, additional proteomic studies are critically needed to illuminate the underlying mechanisms of cognitive impairment syndromes in people with type 2 diabetes, so to identify proteins that can be used as biomarkers of risk. The overarching goal of this pilot project is to use proteomic analyses to examine differences in plasma proteins and protein networks in people with type 2 diabetes, who do and do not develop mild cognitive impairment, as a first step toward identifying potential risk biomarkers for cognitive impairment syndromes in people with type 2 diabetes. First, to achieve this goal, our primary aim is to identify proteins associated with newly diagnosed mild cognitive impairment in people with type 2 diabetes (Aim 1). Additionally, we aim to provide further depth to our understanding of the molecular mechanisms driving the underlying neuropathology of mild cognitive impairment in people with type 2 diabetes. Thus, we will determine whether proteins associated with mild cognitive impairment in Aim 1 also relate to preclinical plasma-based biomarkers of neurodegenerative disease and Alzheimer’s disease neuropathology in people with type 2 diabetes (Aim 2). Results from this pilot study will reveal potential mechanisms by which people with type 2 diabetes develop cognitive impairment syndromes. Thus, providing important insights that could inform use of plasma- derived protein biomarkers for risk stratification of people with type 2 diabetes, and possible protein targets for development of novel therapeutics and treatment strategies to mitigate risk of cognitive impairment syndromes in people with type 2 diabetes.