The Role of Chemical Exposures in Alzheimer's Disease (AD) and its Trajectory

About This Grant

ABSTRACT It has become increasingly clear that environmental exposures, the genome, gut microbiome, diet, and lifestyle all affect an individual’s metabolic state contributing to brain health and disease, including Alzheimer’s disease (AD) and AD-related dementia (ADRDs). Our AD Metabolomics Consortium (ADMC), in collaboration with the AD Neuroimaging Initiative (ADNI), is applying state-of-the-art metabolomics and lipidomics technologies combined with genomic and imaging data to map metabolic failures across the spectrum and trajectory of AD- ADRDs. The ADMC is part of the Accelerating Medicines Partnership for AD (AMP-AD), a flagship precompetitive partnership that brings government, industry, and nonprofit organizations together to transform the current model for developing new AD diagnostics and treatments. Our work confirmed that peripheral metabolic changes, influenced by the exposome, inform about cognitive and brain imaging changes and ATN markers for disease, highlighting peripheral and central changes are connected in part, through the metabolome. The Alzheimer Gut Microbiome Project (AGMP) that we launched in partnership with ten AD Research Centers (ADRC) and large diet and lifestyle interventions (POINTER, MIND, BEAT-AD) aims to define the influences of the gut microbiome, diet, and gut-brain axis in AD. This research infrastructure is building the first AD molecular atlas that captures exposome influences on AD-associated metabolomic profiles. Five metabolomic centers of excellence are completing a ring trial to identify environmental chemical exposures, dietary components, and drug signatures that when linked to gut microbiome and metabolomic data will define exposome profiles associated with AD/ADRDs. In this U01, we leverage a large NIA-funded collaborative infrastructure, connections to 10 ADRCs, and access to unique community-based longitudinal cohort studies and biobanks (FHS, ROSMAP, Rotterdam, UK Biobank) to: (i) expand coverage of the chemical exposome in blood and brain, and (ii) link identified signatures to brain aging, incident dementia, and AD. Human data generated in this project will inform and be informed by results from complementary preclinical exposome studies in AD mouse models (AG-24-023) and cell-based systems (AG-24-241). A long-standing partnership with Sage Bionetworks allows for rapid sharing of exposome data collected under this application through the AD Knowledge Portal. We will leverage data generated under the AMP-AD, AGMP, and this U01 to enable data harmonization with existing data generated in the AMP-AD and AGMP with the goal of integrating of complex exposure data across multiple cohorts. This project provides an unparalleled opportunity to create a deeper understanding of how the exposome interacts with genetics, gut microbiome, and metabolome to modulate AD pathogenesis, potentially leading to novel therapeutic approaches and preventative measures for AD that address ethnic, socioeconomic, and geographic diversity. Our European and USA partners connect us with large exposome initiatives including in the Netherlands and “The Human Health Exposure Analysis Resource” (HHEAR) network.