Delineating the role of the gut microbiota and its derived metabolites in the development of dementia in multi-ethnic populations

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Abstract. Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), with a worldwide prevalence of 50 million in 2018, will surpass cancer as the leading cause of death by 2040. However, efforts to prevent, cure, or even treat AD/ADRD have been unsuccessful. Genetic, blood, and MRI biomarkers can be used for risk stratification, but there are limited disease-modifying options for those at high risk. Moreover, while ethnic differences in AD/ADRD prevalence have been reported, patients of minority ethnoracial groups often receive delayed diagnosis or inadequate treatment options. Thus, efforts are needed to identify modifiable risk factors that could stratify the population at risk, reverse the disease course, and determine novel biomarkers for understudied populations. The gut microbiota, a modifiable risk factor, has been shown to interact with the central nervous system through the bidirectional gut-microbiota-brain axis and thus, affecting brain physiology and pathology. In this application for a K01 award, Dr. Bernard Fongang, a Bioinformatician at the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and the South Texas Alzheimer's disease Research Center will leverage data from two cohorts to study the association between the gut microbiome and AD/ADRD endophenotypes. In Aim 1, he will examine whether the gut microbiota features (bacteria abundance and diversity) are related to various neuroimaging and neurocognitive markers of AD/ADRD, using data from the Framingham Heart Study and the Texas Alzheimer's Research and Care Consortium (TARCC). In Aim 2, Dr. Fongang will assess the plasma metabolomics profiles of these markers. Finally, in Aim 3, he will use integrative omics methods and sophisticated mathematical models to identify the microbiota-derived metabolites related to neuroimaging and neuropsychological markers of ADRD and how they are linked with incident AD. The large proportion of Hispanics within the TARCC study population will also allow for examining differences by ethnicity and sex. The results of this study will serve as the foundation for an R01 grant application, to be completed by year 3 of the award. Along with funding for this innovative and important research, this K01 will provide Dr. Fongang with the support necessary to achieve his goal of becoming an independently-funded leader in identifying novel biology and novel drug targets to accelerate drug development for ADRD. Dr. Fongang has assembled a mentoring team comprised of Dr. Sudha Seshadri, founding director of the Biggs Institute, as the primary mentor, and three co-mentors: Dr. Joseph Petrosino, an expert in human microbiome; Dr. Patrick Sung, Chair of Biochemistry and structural biology with extensive mentoring experience; and Dr. Xianlin Han, an expert in lipidomics and metabolomics. In collaboration with his mentoring team, he has also developed a detailed plan of coursework and readings to help him achieve his research- and career-based goals.