This is a competitive renewal application for grant R01AG050440 (Diabetes and Brain Amyloid in Middle Aged Hispanics; 09/01/15-05/30/21). The goal of this project is to examine whether type 2 diabetes (referred to as diabetes from here on) and it’s antecedent, pre-diabetes, are associated with higher brain amyloid ß (Aß) burden, the main neuropathologic feature of Alzheimer’s disease (AD), compared with persons with normal glucose tolerance (NGT). We ascertained Aß in vivo using 18F-Florbetaben positron emission tomography (PET) in 350 late middle-aged Hispanics from New York City, aged 64.15 ± 3.34 years of age at the time of recruitment, (72% female). We also conducted 3T brain magnetic resonance imaging (MRI) to ascertain neurodegeneration and cerebrovascular disease (CVD), and 18F-MK6240 PET to ascertain tau, allowing to assess the three main constructs in the 2018 National Institute on Aging (NIA)/Alzheimer’s Association (AA) research framework, amyloid, tau, and neurodegeneration. We have had two key findings that form the basis for this renewal application: (1) Pre-diabetes, but not diabetes, is associated with higher brain Aß in cross-sectional, and longitudinal analyses. The lack of association between diabetes and higher brain Aß as compared with pre- diabetes is in part explained by diabetes treatment, which was related to lower brain Aß among participants with elevated glycemia (pre-diabetes and diabetes); (2) Females have higher brain Aß and tau burden as compared with males in cross-sectional analyses, although females have less neurodegeneration and better verbal memory compared with males. The cohort is now completing its 2nd wave of assessments (target: 315 participants). We propose to complete two more waves of brain imaging at intervals of approximately 24 months with an expected attrition rate of 10% per wave (wave 3: 284 participants; and wave 4: 256 participants), with improved characterization of diabetes transitions, diabetes medication use, gynecological/obstetrical history in women, sex hormonal profile, plasma AD biomarkers, and cognitive adjudication. In total, we will have four waves of ascertainment of Aß, tau, and neurodegeneration in brain imaging and plasma at the end of the project, spanning the 7th and 8th decades of life. Aim 1 is to compare changes in Aß among persons with NGT, pre- diabetes/untreated diabetes, and treated diabetes. We will also examine changes in tau, neurodegeneration, CVD, and cognitive performance as outcomes. We will also examine diabetes category transitions (e.g. NGT to pre-diabetes) and treatment status as exploratory exposures. We will also explore how sex and APOE-e4 modify these associations. Aim 2 is to examine the longitudinal association of sex with changes in Aß. We will also examine changes in tau, neurodegeneration, CVD, and cognitive performance as outcomes. We will explore whether sex hormonal profile and gynecological and obstetrical history mediate these associations. The ...