Gut microbiome-related metabolites and cognitive impairment

Abstract Cognitive impairment is a significant source of neurological disability, and a majority of cases are caused by vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD). Differences in the incidence among Black individuals compared to White individuals lead to a disproportionate burden of cognitive impairment in this group. The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study is a longitudinal multi-racial study of 30,239 community-dwelling participants designed to enhance the understanding of these conditions and identify potential contributors to racial disparities. Using our metabolomics platform, our previous studies have shown that metabolites are independent risk factors for stroke and many of these markers are synthesized by gut microbiota. Our studies further highlighted that metabolites can illuminate racial differences in disease risk, and that gut microbiome-related metabolites are modifiers of the relationship between dietary intake and stroke. In the current proposal, we will expand upon our findings and unravel the relationships between gut microbiome-related metabolites, VCID and AD biomarkers, and subsequent cognitive impairment. We seek to address our hypothesis in the following aims in the REGARDS study, with replication in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort: 1. To examine the association between gut microbiome metabolites and CSVD brain MRI phenotypes in REGARDS and CARDIA, and assess for differences by race. 2. To determine the association between gut microbiome-related metabolites and the incidence and trajectory of cognitive impairment. 3. To determine the association between biomarkers of brain amyloid β (Aβ+) status and cognitive impairment in REGARDS, and assess for effect modification by gut-related metabolites. Collectively, these aims will provide insight into the relationships between diet and circulating metabolites on the progression to cognitive impairment through CSVD and Aβ+ pathways. Our multidisciplinary collaboration includes investigators who bring collective expertise in metabolite profiling, imaging markers of VCID, epidemiology cohort studies, cognition and aging, and health disparities. Identifying markers that provide insight in these mechanisms may provide actionable leads for future interventional studies, inform personalized treatment targets, and ultimately may lead to novel gut microbial engineering therapeutics.