Project Summary/Abstract A significant gap in understanding is how suboptimal control of hyperglycemia from type 2 diabetes (T2DM) and prediabetes, particularly in young adults (18-45), influences later-life cognitive decline and Alzheimer’s dis- ease and related dementias (ADRD) risk. This gap is a critical barrier to developing T2DM prevention and management interventions for reducing vascular contributions to cognitive impairment and dementia (VCID). Hyperglycemia increasingly develops in younger adults and may impair their cognition. The central hypothesis is that higher cumulative hyperglycemia levels over the life course and subopti- mal T2DM management contribute to faster cognitive decline and higher ADRD risk. Guided by robust prelimi- nary data, the team will test this hypothesis using 3 specific aims. Aim 1 will quantify the influence of cumula- tive hyperglycemia from young adulthood to late life on cognitive trajectories and ADRD in adults with and with- out T2DM, and explore how sex, race, and hyperglycemia duration affect these relationships. Aim 2 will deter- mine the impact of T2DM management (cumulative hemoglobin A1c levels) on cognitive trajectories in adults with T2DM, and explore how sex, race, and T2DM duration affect these relationships. Aim 3 will identify poten- tial mechanisms for T2DM-related ADRD. It will clarify the relationships between cumulative hyperglycemia and magnetic resonance imaging markers of cerebral small vessel disease in adults with and without T2DM, determine how much cerebral small vessel disease burden explains associations between cumulative hyper- glycemia levels and cognitive decline and incident ADRD, and explore the role of stroke. Aims 1 and 3 will use pooled cohort studies to measure the effects of glycemia and other vascular risk factors, cerebral small vessel disease, and stroke on ADRD risk. Aim 2 will use an individual participant data meta-analysis of 3 trials to quantify the effects of T2DM management and control of other vascular risk factors on cognitive trajectories. The multi-disciplinary research team has the proper expertise and a strong record of executing multi- center pooled cohort studies of VCID. The study is innovative because it includes young adults and those with prediabetes, and it will create new pooled datasets with unprecedented size and diversity in age, sex, geogra- phy, race, ethnicity, and hyperglycemia duration for VCID research. Aims 1 and 2 will provide crucial evidence on optimal control of glycemia and other vascular risk factors to reduce ADRD risk in people with T2DM and prediabetes, especially in younger adults. Aim 3 will identify potential mechanisms for VCID interventions. The study is significant because it will generate empirical evidence to guide future trials, shared decision-making in clinical practice, clinical guidelines, and health policies to preserve cognitive health and prevent VCID in adults with hyperglycemia. Over the long term, this kno...