Abstract Increased risks of chronic illnesses, including Alzheimer’s Disease and related dementias (AD/ADRD), have been linked to exposures to ambient air pollution, particularly fine particulate matter (PM2.5). Despite the observed epidemiological evidence, central and unsolved questions remain on what components of PM2.5 (e.g., sulfate, nitrate, ammonium, elemental carbon, organic carbon, metals, etc.) are most neurotoxic and how they contribute to the observed risk of developing AD/ADRD. A better understanding of the specific exposure components and underlying causal biological mechanisms and pathways revealing the link between PM2.5 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 epigenomics, proteomics, and metabolomics can be used to sensitively map internal biological perturbations following exposures to PM2.5. We propose deeper molecular profiling to investigate the molecular connections underlying the neurotoxicity of individual PM2.5 pollutants and mixtures using high resolution spatio-temporal modeling of PM2.5 components as well as targeted and untargeted profiling of PM2.5 toxicants in blood, cerebrospinal fluid (CSF), and brain tissue. The body’s biological response to these toxicants will be determined by measuring perturbations in DNA methylation, proteins, and metabolites in the same tissues. Our study will be based on three well- characterized, diverse cohorts with comprehensive assessment of AD/ADRD and related indicators and biomarkers. Participants come from two longitudinal cohort studies prospectively followed at biennial clinical visits and a brain bank from the same study area. They span a wide range of age and cognitive status and reflect the racial diversity of Georgia (i.e., 32% African American). Replication of significant findings will be done in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We will 1) characterize individual exposures to chemical and metal components of PM2.5 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 PM2.5 toxicants (modelled individually and as mixtures) and how they manifest in CSF and blood of individuals with versus without AD/ADRD; 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 PM2.5 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 air pollution-related risk for AD/ADRD. Moreover, it provides a critical opportunity to enrich deeply phenotyped AD/ADRD cohorts with state-of-the-art exposure assessment and omics profiling to understand the environmental impact on AD/ADRD.

PROJECT NARRATIVE Despite the observed epidemiological evidence linking fine particulate matter (PM2.5) exposures and Alzheimer’s Disease and related dementias (AD/ADRD), we still lack a deep understanding of the neurotoxicity of the specific PM2.5 components and the molecular mechanisms involved. By using innovative targeted and untargeted exposure assessment, single- and multi-omics analysis, and cross-tissue approaches, our primary objective is to offer valuable insights into how individual PM2.5 pollutants and mixtures interact with biological responses across epigenome, proteome, and metabolome, ultimately contributing to our understanding of AD/ADRD. This knowledge can aid future endeavors aimed at shaping environmental regulations and health policies to reduce the risk of AD/ADRD associated with air pollution.