ABSTRACT Given the aging of the population, Alzheimer's disease (AD) is a major public health issue. Because of the lack of effective interventions to date, there is a need to identify new treatments. Emerging evidence has shown that AD involves multiple pathological mechanisms, with combinations of various forms of vascular and AD pathology. The renin angiotensin system (RAS) plays a key role in blood pressure (BP) regulation and there is growing evidence about its likely involvement in the pathogenesis of AD, potentially through BP control and associated improvement of cerebral blood flow (CBF) and vascular endothelial function, but also through other mechanisms, including antioxidant, and anti-inflammatory effects, in addition to modulation of amyloid and tau metabolism. There are very few studies, including our studies, evaluating the role of RAS in cognitively normal at-risk population to evaluate associations between RAS peptides, structural brain changes and cognitive function, and none following participants over long period of time. In this study we propose to extend our previous research in cognitively normal participants who are obese with T2DM, thus at increased risk for AD , from Look AHEAD (Action for Health in Diabetes) study by measuring RAS peptides to elucidate the underlying mechanism by which the RAS may be involved in structural brain changes affecting cognitive function over an 9-14-year period. The Look AHEAD study was a randomized clinical trial of a lifestyle intervention that is now in an observational phase. Look AHEAD is ideal for the proposed study because of the high prevalence of vascular risk factors (diabetes mellitus, obesity, hypertension, dyslipidemia) as well as 1) stored blood samples and 2) ancillary studies with detailed measures of cognitive function and structural MRI imaging available. Our aims are to examine 1) change of blood RAS peptide and enzyme levels (ACE-1, ACE- 2, ANGII, ANGIII and ANG1-7) over time (collected at years 1 and 4); 2) associations between blood RAS enzyme and peptide levels and brain MRI structural measures related to AD signature regions and vascular measures (collected once through years 9-11); and 3) associations between blood RAS enzymes and peptide levels and global and domain specific cognitive measures (collected longitudinally through years 8-14). In this proposal we aim to elucidate the role of RAS during aging to understand its contribution in the development of AD using cross-disciplinary approach. The results of this study will help understand the relationship between RAS and brain biomarkers and guide future research to examine whether changes in these peptides could serve as predictors of cognitive decline and/or cognitive impairment.