Assessing the longitudinal impact of Mediterranean diet interventions to reduce cognitive decline on gut microbiota composition and bile acid variety

/ABSTRACT Alzheimer’s disease is a progressive neurodegenerative disorder with a complex etiology affecting over six million individuals in the United States alone, with numbers projected to rise significantly as the population ages. Concomitant changes in gut microbiome and metabolome composition have been observed over the course of Alzheimer’s-related cognitive decline, suggesting host microbiota may mediate the pathophysiological processes of Alzheimer’s disease and related dementias. Gut microbes contribute to host metabolism through the production and modification of metabolites, such as bile acids, which collectively influence overall metabolic health. Lifestyle interventions, such as diet modification, are promising strategies for lowering dementia risk, and these modifications are also influential in regulating the gut microbiome. However, the long-term effects of specific dietary interventions on microbially-mediated bile acid profiles and their impact on cognitive decline remain poorly understood, motivating further investigation. This proposal seeks to apply advanced computational and algorithmic approaches to identify compositional and functional changes in the gut microbiome and metabolome over the course of longitudinal dietary interventions. Aim 1 of this proposal will unify three independent cohorts assessing the impact of adherence to the Mediterranean diet, a diet high in plants and healthy fats, on cognitive decline. By conducting phylogenetically-aware metagenomic analyses and network-based untargeted metabolomic analyses, this proposal aims to identify changes in microbial communities and bile acid profiles during Mediterranean dietary interventions, and correlate these changes with host phenotypes indicative of Alzheimer’s risk. Complementarily, Aim 2 of this proposal will assess the prognostic potential of gut microbiome and metabolome features by constructing and evaluating machine learning models to predict cognitive outcomes over the course of intervention. These efforts will deepen our understanding of the relationship between diet, the gut microbiome, bile acid proliferation, and cognitive health by employing standardized and reproducible methodological analyses across large cohorts. Ultimately, this research is poised to reveal mechanistic targets for future study, facilitating the development of novel diagnostic and therapeutic strategies for Alzheimer's disease in at-risk populations. Project Number: 1F30AG094275-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Lucas Patel | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $43,784 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F06B-T (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11316523