Data Infrastructure and Molecular Atlas for Alzheimer's Disease: Connecting Exposome, Gut Microbiome, and Metabolome

Molecular mechanisms of neurodegenerative and neuropsychiatric diseases are poorly understood including for Alzheimer disease and related dementias. Repeated failures of clinical trials illustrate our limited knowledge about disease and its heterogeneity and trajectories. It has become increasingly clear that the genome, gut microbiome, diet, lifestyle socioeconomic status and environmental exposures can all impact an individual’s metabolic state, and this can contribute to brain health and disease. Our Alzheimer Disease Metabolomics Consortium (ADMC) that is part of Accelerating Medicine Partnership for Alzheimer Disease (AMPAD) and in partnership with Alzheimer Disease Neuroimaging Initiative (ADNI) has applied state of the art metabolomics and lipidomics technologies combined with genomic and imaging data to map metabolic failures across the trajectory of the disease. Our studies confirmed that peripheral metabolic changes influenced by exposome do inform about cognitive changes, brain imaging changes and ATN markers for disease confirming that peripheral and central changes are connected in part through the metabolome. The Alzheimer Gut Microbiome Project 1U19AG063744 that we also lead launched two years ago and in partnership with ten Alzheimer Centers (ADRC) and large diet and life style intervention studies (Pointer MIND BEAT) aims to define the influences of gut microbiome and the gut brain axis in Alzheimer Disease. We have illustrated that several gut bacterially produced metabolites are present in human brains and do correlate with cognitive decline and mood changes in AD. In this Administrative Supplement application, we propose to build research infrastructure that can lead to the creation of a first molecular atlas for AD that captures influences of the exposome with metabolome as readout and where we enable through a partnership with Sage Network secure and rapid sharing of all exposome data collected under the U19 mechanism. Specially, we propose to expand metabolomics coverage of the exposome to capture environmental chemical exposures, food intake components and signatures of drugs and supplements that will be added to gut microbiome data. We will also set the stage and through a partnership with Wisconsin team that led the creation of the Neighborhood Atlas for creating

enabling mechanisms for capturing in near future molecular  influences of socioeconomic status and geolocation. This expanded coverage of the exposome and its influences on metabolism presents an unparalleled opportunity to create deeper understanding of AD pathogenesis connecting influences of exposome, genome, gut microbiome and metabolome and leading to novel therapeutic approaches addressing issues of ethnic diversity and neighborhood disadvantage. Our European partners in the U19 are already applying successfully such approaches that will inform our initiative with links established to USA “The Human Health Exposure Analysis Resource” (HHEAR) network.