Increased risks of chronic illnesses, including Alzheimer’s Disease and related dementias (AD/ADRD), have been linked to exposures to ubiquitous environmental exposures like ambient air pollution. A better understanding of environmental risk factors for AD/ADRD and underlying causal biological mechanisms revealing the link between environmental toxicants and AD/ADRD will provide valuable insight into disease etiology and pathophysiology and inform environmental regulation and health policy to reduce disease burden of AD/ADRD. Although omics applications in environmental health research are still nascent, several studies conducted by our team and others demonstrate that various single omics approaches, including genomics, epigenomics, proteomics, and metabolomics can be used to sensitively map internal biological perturbations following exposures to environmental exposures. We propose to investigate the molecular connections underlying the neurotoxicity of environmental toxicants leveraging the extant data and resources in the UK Biobank. The body’s biological response to these toxicants will be determined by measuring perturbations in different omics layers, including DNA methylation, gene expression, proteins, and metabolites. We will 1) characterize individual exposures to environmental toxicants and determine their impact on AD/ADRD risk; 2) elucidate patterns of biological perturbations in single- and multi-omics signatures of the brain associated with environmental exposures and how they manifest in individuals with various degrees of AD/ADRD risk; and 3) determine the relative contribution of environmental and genetic factors to AD/ADRD risk. This study provides a critical opportunity to address research gaps in molecular mechanisms underlying environmental toxicants neurotoxicity and their role in the development of AD/ADRD, supporting future efforts that aim to inform environmental regulation and health policy to mitigate environment-related risk for AD/ADRD
