Investigating the relationship between age-related skeletal muscle insulin resistance and cognitive impairment

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Abstract In this ADRD supplement, we propose to expand the scope of work in Aim 1 of our NIH/NIA 1R15AG073922 (expires 2024). The scope of work in the funded R15 centers on understanding the cellular mechanisms in skeletal muscle that contribute to age-related insulin resistance. Specifically, Aim 1 of the parent grant examines mechanisms contributing to age-related skeletal muscle insulin resistance at the level of AS160 phosphorylation, the most distally located protein in the insulin signaling cascade. Alzheimer’s disease and Type 2 diabetes are currently ranked amongst the top 7 causes of death for individuals over the age of 65 years (CDC). Insulin resistance has been well-recognized as the primary contributor for the development of type 2 diabetes. Similarly, mild cognitive impairment is often a precursor for the development of Alzheimer’s disease. While each condition has been traditionally thought of as the early pathogenesis for their respective disease, growing evidence suggests that insulin resistance plays a critical role in the development of cognitive impairments leading to Alzheimer’s disease. Insulin resistance has been reported in older adults with mild cognitive impairment and Alzheimer’s disease. Additionally, insulin resistance has been associated with brain atrophy in regions affected by early Alzheimer’s disease. Skeletal muscle is the main target of insulin-mediated glucose uptake; therefore, it is the ideal tissue to investigate the relationships between age-related skeletal muscle insulin resistance and cognitive impairment. Unfortunately, no known research has investigated the relationship between the skeletal muscle mechanisms contributing to age-related insulin resistance (parent grant) and cognitive impairment; therefore, we propose two proof-of principal specific aims to examine the nexus between these critically important conditions negatively impacting the aging process. Aim 1 will determine if impaired skeletal muscle insulin-stimulated AS160 phosphorylation is related to reduced cognitive domains of learning/memory, psychomotor processing speed, and executive functioning in older adults, and whether older adults with MCI will have lower AS160 phosphorylation compared to older adults that are cognitively normal. Aim 2 will determine if impaired skeletal muscle insulin-stimulation of AS160 phosphorylation is associated with biomarkers of cognitive impairment (p-181 tau, neurofilament light chain, beta-amyloid-42, acylcarnitines, and the apoE4 allele). To accomplish these aims we will add a cohort of older adults with MCI (n=12) to the proposed scope of work in the parent grant and add cognitive function testing and genetic apoE4 allele testing to all aged adults enrolled during the 1-year supplement (n=12 aged MCI and n=12 aged cognitively healthy from parent grant). Further, all stored blood (n=12 aged MCI from supplement, n=12 aged and n=12 young cognitively healthy from parent grant) will be tested for biomarkers of cognitive impairment. At the completion of this supplement, we expect to have provided proof-of principal demonstrating a link between impaired skeletal muscle glucose metabolism, specifically impaired insulin-stimulated AS160 phosphorylation and cognitive impairments. Additionally, this supplement will provide an opportunity for students to be exposed to translational and multidisciplinary research, while learning about the age-related health concerns.