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

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PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease related dementias pose an enormous public health challenge. In the absence of a cure, prevention or delay of pathology offers the most promising avenue to control the disease. Despite growing recognition that cardiometabolic risk factors are major contributors to cognitive decline, Alzheimer’s disease, and Alzheimer’s disease related dementias, many gaps remain in our understanding of the mechanisms and pathways between glucose homeostasis and cognitive function. While type 2 diabetes (T2D) is increasingly recognized as a major preventable risk factor for Alzheimer’s disease and related dementias, intensive glucose control in T2D has not been shown to prevent cognitive decline in trials. This finding and inconsistent results for the influence of glucose control (HbA1c) on cognitive decline pose the question: What aspects of dysglycemia, and its inverse glucose homeostasis, increase the risk of Alzheimer’s disease or related dementias? This study’s overall goal is to investigate the role of dysglycemia across the glucose spectrum on incident neurocognitive markers of Alzheimer’s disease and Alzheimer’s disease related dementias in a multi-ethnic cohort: The Multi-Ethnic Study of Atherosclerosis (MESA). MESA enrolled 6814 men and women beginning in 2000. MESA participants have been extensively studied with respect to cardiovascular risk factors and outcomes and MESA-MIND, a cognitive ancillary, adds comprehensive cognitive testing and neuroimaging including brain MRI and amyloid β PET scans. MESA has a 7th exam occurring between 2021-2023 that will be concordant with the second MESA-MIND visit. While fasting glucose was obtained at every exam, and HbA1C and HOMA-IR measured at some exams, continuous glucose has not been measured. Adding continuous glucose monitoring wearable technology to MESA Exam 7 and repeated two years later provides a unique and timely opportunity to answer challenging questions about the role of dysglycemia that continue to impede the development of successful prevention strategies for Alzheimer’s disease and Alzheimer’s disease related dementias. This study will also add new measurements of insulin resistance (HOMA-IR). This ancillary to MESA will 1) Investigate the antecedent determinants of glucose homeostasis (from continuous glucose monitors at Exam 7 (n=2000) and change over two years (n=1000), 2. Determine whether continuous glucose markers of glucose homeostasis, dysglycemia, and change over time are associated with incident neurocognitive indicators of Alzheimer’s disease or Alzheimer’s disease related dementias (n=2000), and 3. Investigate the contributions of dysglycemia to Alzheimer’s disease and related dementia pathologies by sex and race/ethnicity (n=2000). Findings from this research will identify new mechanisms for the development of Alzheimer’s disease and Alzheimer’s disease related dementias, discover new primary and secondary prevention targets, and have the potential to change clinical care.