Glucose homeostasis and the risk of Alzheimer's disease and Alzheimer's disease related dementias in the Multi-Ethnic Study of Atherosclerosis

Type 2 diabetes (T2D) is a key modifiable risk factor for cognitive decline, and increases the risk for Alzheimer’s disease and related dementias (ADRD). Prediabetes has also been associated with steeper cognitive decline, suggesting a more continuous risk from dysglycemia, but results for glucose in the normoglycemic range have been less consistent. The high prevalence of dysglycemia (25% for T2D and 48% for prediabetes) in adults >65 suggests the glucose/cognition relationship has a major public health impact in our aging population. Intensive glycemic control in T2D has not been shown to prevent cognitive decline in trials, despite the observational indications that higher glucose level within T2D may play a role. This contrasting evidence leads us to pose the essential question: What aspects of dysglycemia increase cognitive risk? Similar gaps in the literature about the role of hypoglycemia in the development of dementia further support the need for more detailed data to fully investigate the effects of dysglycemia on cognitive trajectories and determine mechanisms of resilience in aging. The proposed research will improve understanding of the role that dysglycemia and type 2 diabetes (T2D) play in the development of cognitive function and decline. Specifically, this proposal focuses on determining which aspects of dysglycemia increase cognitive risk, and what determines cognitive disparities by sex and race/ethnicity. The primary objectives of this research are to investigate: 1. The determinants of glucose regulation, 2. The association between glucose control, beyond HbA1c, and cognitive function, and 3. The heterogeneity in cognitive decline by sex and race/ethnicity. The primary data collection aspect of this proposal, including measuring HOMA-IR and HbA1c; having MESA participants wear a continuous glucose monitor (once at Visit 7 for n=2000 and a second CGM for n=1000 2 years after Visit 7); complete a diary of sleep, exercise, and meal times; and complete an abbreviated cognitive assessment by phone or video (n=2000 2 years after Visit 7) is essential to achieve these objectives.