Early life glycemic status and Alzheimer's disease neuroimaging markers in middle age: the Bogalusa Heart Study

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The U.S. population greater than 65 years of age is estimated to grow from 46 million in 2014 to 88 million in 2050, and that growth has paralleled dramatic increases in prevalence of Alzheimer's disease (AD) and other late life cognitive syndromes. To date, there is no effective treatment to stall or reverse late life cognitive decline. Therefore, prevention, through modification of risk factors, is an essential strategy. Metabolic dysfunction, which often culminates in a clinical diagnosis of type 2 diabetes mellitus (T2DM) or pre-T2DM, is one such modifiable risk factor that is highly prevalent. However, while metabolic dysfunction itself is modifiable, it is not clear how to optimally prevent adverse and potentially long-lasting effects of metabolic dysfunction on the brain. The knowledge gap driving this uncertainty is incomplete understanding of the complex, bi-directional relationships between peripheral and central mechanisms of neuronal injury associated with metabolic dysfunction. Adverse health behaviors (e.g., poor diet and inadequate physical activity) induce adverse peripheral changes (e.g., insulin resistance, chronic hyperglycemia) as well as adverse brain changes (e.g., glucose hypometabolism, amyloid accumulation, and cerebrovascular dysfunction). Brain changes culminate in adverse cognitive changes that in turn may promote the adverse health behaviors. It has been long recognized that early life factors can have lasting consequences, yet it is unknown whether glycemic status in childhood and adolescence is an important trigger of cognitive changes decades later, and whether such cognitive changes are driven by AD-related neurobiological substrates like amyloid. The Bogalusa Heart Study (BHS) is the only on-going, life-course study of a biracial (35% African American/65% white; 13% T2DM, 35% pre-T2DM) U.S. population, with detailed, prospectively-collected assessments of metabolic status from early childhood through mid-life, and cognitive performance data at two time points in midlife (average age of 45 years) among 1,298 men and women. This project will use neuroimaging and cognitive testing to explore long- term cognitive outcomes (among 600 BHS participants) associated with high-normal early-life mean Fasting Plasma Glucose (mFPG), as well as AD-related neurobiological substrates for these outcomes (a subset of 250 BHS participants will also undergo 3T brain MRI and PET). The results of this study could impact FPG guidelines among adolescents and whether glycemic treatment should to be initiated avoid long-term adverse brain outcomes. The project will also assess whether AD-related molecular targets may be modified to block the impact on the brain of early life high-normal mFPG.