Metformin Beyond its Therapeutic Effect on Glucose Metabolism to Ameliorate Altered Brain Function and Cognition in People with Insulin Resistance - PROJECT SUMMARY Emerging evidence shows that insulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) and related dementias. Understanding of the mechanistic link between IR and cognitive decline is critical to develop therapeutic approaches to prevent and ameliorate dementia in IR. Eighty percent of individuals with AD exhibit IR, suggesting a critical role for metabolic dysfunction in disease pathogenesis. Our pre-clinical studies show that IR impairs brain mitochondrial function resulting in reduced ATP production and increased ROS emission, but these adverse effects are reversed by aerobic exercise and metformin by improving insulin sensitivity. Further, IR mouse models induced by high-fat diet or neuronal insulin receptor knockout results in mitochondrial dysfunction and cognitive deficits. We propose that reduced ATP production may slow down synaptic activity and large-scale brain network connectivity essential for cognition. Further, in IR ROS unopposed by endogenous antioxidant defense may damage proteins causing atrophy of brain regions critical for cognition. Supported by an NIA R21 pilot study, we showed that 40 weeks of metformin, a commonly used therapeutic agent, improved insulin sensitivity, increased brain glucose uptake, preserved brain volume and connectivity, and improved processing speed and working memory in older IR adults. Building on these findings, we propose a randomized, double-blind, placebo-controlled, multi-site trial to evaluate whether metformin improves cognitive function in older adults with IR by enhancing brain glucose metabolism, structural integrity, and functional connectivity. We will recruit 195 60-85 years old IR participants, across three clinical sites (Mayo Clinic Rochester and Jacksonville, and University of Minnesota) and they will be randomized in a double-blind way to receive either maximally tolerated doses of metformin or placebo for 48 weeks. Both metformin and placebo group will receive Vitamin B12 supplement to avoid the reported confounding effect of B12 deficiency on metformin use. In Aim 1, we will determine whether metformin improves cognitive performance, including processing speed, working memory, and global cognition, using the NIH Toolbox Cognition Battery. In Aim 2, we will assess whether metformin preserves or increases brain regional volume and functional connectivity, particularly in the hippocampus and frontal and temporal lobes, using volumetric MRI and resting-state functional MRI. In Aim 3, we will evaluate whether metformin increases glucose uptake in cognition-related brain regions using 18F-FDG PET, and whether these metabolic changes are associated with improvements in brain structure, connectivity, and cognition. We submit that the proposed study is sufficiently powered based on robust preliminary data to address our specific aims and will provide novel insights into the neurobiological mechanisms linking IR to cognitive decline and evaluate metformin as a potential therapeutic strategy to prevent or delay dementia in a high-risk aging population. The proposed work leverages harmonized imaging protocols and established collaborations across three clinical sites to address a critical gap in dementia prevention research.
