Towards Precision Nutrition for Alzheimer's Dementia Prevention: A Prospective Study of Dietary Patterns, the Gut Microbiome and Cognitive Function

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PROJECT SUMMARY This proposal directly addresses a high-priority research topic, “Enabling precision medicine for Alzheimer’s disease and related dementias through deep molecular phenotyping”, for PAR-19-070, Research on Current Topics in Alzheimer's Disease and Its Related Dementias, by beginning to develop precision dietary approaches for AD prevention through integrating multiple molecular data types. The potential for healthy dietary patterns to maintain cognitive health is supported by cohort studies and a randomized trial. However, these healthy dietary patterns were developed based on population averages and may not be best suited for a given individual. Preliminary data from our group and others support the rationale to study personalized approaches tailored to individual gut microbiomes to improve dietary prevention of Alzheimer’s dementia (AD). However, no study has examined modifying and mediating roles of the gut microbiome in the diet-cognition association. The few human studies of the gut microbiome in AD were limited by small size, cross-sectional design, and lack of high-resolution microbial functional profiling. This background supports our central hypotheses that 1) healthy dietary patterns contribute to cognitive health partly through modulating the gut microbiome; and 2) associations of the dietary patterns with cognitive function vary by individuals’ gut microbial profiles. This proposal represents a highly cost-efficient, prospective study leveraging existing fecal samples/microbiome data and cognitive function assessments in three studies with complementary strengths in study design, and diet and outcome assessments: the Nurses’ Health Study II (NHSII, n =1,500) with decades-long repeated dietary assessments and extended follow-up, the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) Trial with randomized dietary interventions (n =604), and the ASPREE-XT Study (n =13,000) with adjudicated incident AD endpoints. To gain more advanced mechanistic insights, we will take a multi’omic approach to combine shotgun metagenomics and metatranscriptomics to profile the microbial composition and enzymatic function, and fecal metabolomics to measure the microbiome metabolic activity. We will investigate roles of gut microbial composition and enzymatic function in the associations of the Mediterranean diet (MedDiet) and the MIND Diet with cognitive function (Aim 1) and examine the interrelationships among the two healthy dietary patterns, the metabolic activity of the gut microbiome and cognitive function (Aim 2) in the NHSII. We will replicate findings from Aims 1 and 2 in ASPREE-XT and the MIND Trial (Aim 3). This project will generate reproducible, translational evidence on gut microbial and fecal metabolomic features that explain inter-individual heterogeneity in response to healthy dietary patterns and provide foundational knowledge for maximizing the benefits of dietary approaches, discovering novel predictive biomarkers, and ultimately contributing to precision prevention of AD.