Genetics and therapeutics pinpoint link between glucose metabolism and Alzheimer’s disease

About This Grant

Diabetes and dementia have an unexpectedly high rate of comorbidity: individuals diagnosed with diabetes have a 1.4–2.2-fold higher risk of dementia than those without diabetes. The healthcare burden of these diseases also differs by race/ethnicity backgrounds (higher in non-Hispanic Black individuals) and by biological sex (higher in men for diabetes but women for dementia). Epidemiological studies have proposed shared risk factors, metabolic disorders, comorbidities, and genetics to explain this relationship but human research in assessing molecular mechanisms is challenging due to environmental influences. Nevertheless, Dr. Litkowski, the primary investigator of this proposal, provided the first causal genetic evidence between diabetes and dementia in her work with the Million Veteran Program. The long-term goal of this project is to elucidate the mechanism by which impaired glucose metabolism leads to cognitive decline. This proposal integrates human findings with causal testing, and preclinical interventions using a unique discovery pipeline in the Alzheimer’s disease mouse panel (AD-BXD), a genetically diverse model incorporating AD loci known to predict cognitive decline in human populations. The objective is to 1) confirm the genomic region Prdm10 leading to declines in postprandial glucose metabolism in AD susceptible females fed a high fat high sucrose diet and 2) evaluate an anti-diabetes drug, miglitol, on strains deemed to be susceptible to cognitive decline. The hypothesis is that genetic (Prdm10) and pharmacological (miglitol) interventions will modify cognitive resilience. This project will be conducted at the University of Michigan (UM), the #2 public research university (and #4 in overall rank) in the U.S., according to the National Science Foundation, with annual research expenditures of ~$1.77 billion dollars and ~$970 million dollars in federally-sponsored research in 2022. UM is a premier biomedical research institution with first-rate core facility services for its researchers, specifically the Bioinformatics Core, Metabolomics Core, and Transgenic Animal Core, relevant to this proposal. The primary investigator (and trainee) of this proposal (Dr. Litkowski) will have access to the extensive facilities and equipment of the Dr. Kaczorowski Laboratory, including a state of-the-art behavioral suite outfitted for cognitive testing (passive avoidance, Y-maze, contextual fear), a surgical suite, and 2 large animal housing rooms. The proposal includes a detailed training plan for Dr. Litkowski mentored by her sponsor, Dr. Kaczorowski, and co- sponsor, Dr. Bridges, both of whom have previously mentored postdoctoral fellows to become independent investigators. The training plan establishes a timeline for achieving data acquisition proficiency to assess glucose/insulin metabolism and cognition, and for developing and implementing innovative reverse genetics approaches. In summary, successful completion of these aims will define Prdm10 as a causal gene, and miglitol as an effective intervention leading to improved glucose metabolism and resilience to AD-related cognitive decline while at the same time preparing Dr. Litkowski for a career as an independent investigator.