Insulin resistance, amyloid, and memory in normal aging and preclinical AD

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and Type 2 Diabetes (T2D) are two of the most common diseases in older adults and their prevalence is increasing with an aging population. Numerous studies have demonstrated that T2D and insulin resistance are risk factors for AD, and reduced markers of insulin signaling are apparent in brain tissue from those affected by AD. Interestingly, in culture, insulin signaling is protective against A¿-mediated synapse degeneration, and insulin may promote A¿ membrane trafficking and release. This relationship is bidirectional, as A¿ itself can cause decreased insulin receptor expression. These and other molecular studies that demonstrate an interplay between insulin and amyloid provide the rationale for clinical studies to more directly investigate the relationship between amyloid and insulin resistance in humans. The goal of this project is to further understand the relationship between metabolic function, cognition, and cerebral amyloid beta deposition. Post-mortem studies have shown a relationship between insulin signaling and amyloid, and clinical literature supports a role for insulin in cognitive function and memory. We will investigate these relationships in cognitively normal older adults with and without cerebral amyloid. For this project, our cohort will consist of subjects known to be positive or negative for A¿ but without cognitive impairment. A¿ positive subjects are thought to comprise a cohort in the very earliest stages of AD, or "preclinical AD." We will use the gold standard for measuring insulin resistance, the hyperinsulinemic-euglycemic clamp, to assess metabolic function. We will also evaluate cognitive performance in the insulin-stimulated state and determine whether amyloid status and level of insulin resistance affect cognition. This project will build upon studies that show intravenous or intranasal insulin improve memory in various cohorts. By investigating insulin sensitivity in subjects with or without cerebral amyloidosis, we will determine whether these factors influence insulin- mediated cognitive improvement in the very earliest stages of AD.