Air pollution, the blood and brain metabolome and their effects on Alzheimer's disease and related dementias - Abstract Exposures to ambient air pollution, especially fine particulate matter (PM2.5), have been associated with increased risks of many chronic illnesses, including Alzheimer’s Disease and related dementias (AD/ADRD). Identification and understanding the role of modifiable risk factors is essential for AD disease prevention. Despite the observed epidemiological evidence, three central and unsolved questions are 1) what components of PM2.5 (e.g., sulfate, nitrate, ammonium, elemental carbon, organic carbon, metals, etc.) are most neurotoxic, 2) the role of other ubiquitous air pollutants (carbon monoxide (CO), nitrogen dioxide (NO2), and ozone (O3)) which often co-occur with PM2.5, and 3) what biological response occurs in the brain following PM2.5 exposure. A better understanding of the specific exposure components and underlying causal pathways revealing the link between PM2.5 and AD/ADRD will provide valuable insight into disease etiology and pathophysiology and inform environmental regulation and health policy to reduce disease burden. Although omics applications in environmental health research are still nascent, several studies conducted by our team and others demonstrate that the blood metabolome can be used to sensitively map internal biological perturbations following exposures to air pollution. The brain and the blood metabolome have also been shown to play an important role in the development of AD/ADRD. However, most previous studies had limited sample sizes (N<200), and only focused on associations between PM2.5 and the blood metabolome or on associations between the metabolome and AD/ADRD markers. No study has looked at these associations with PM2.5 and AD/ADRD in a cross-tissue analysis of blood and brain to elucidate their interconnections. We propose to investigate the molecular connections underlying the neurotoxicity of individual and mixtures of air pollutants using high resolution spatio-temporal modeling of air pollution mixtures, and untargeted cross-tissue metabolomics approaches in three well-characterized, diverse studies with comprehensive assessment of AD/ADRD and related indicators and biomarkers. Specifically, we will 1) investigate associations between exposures to air pollution mixtures and indicators of AD/ADRD, 2) characterize cross-tissue (blood and brain) metabolomic signatures of air pollution mixtures and indicators of AD/ADRD, and 3) identify early changes in the blood metabolome as potential biomarkers of the neurotoxicity of exposures to air pollution mixtures by leveraging prospective assessments of AD/ADRD risk among cognitively normal individuals. This study provides a critical opportunity to address research gaps in molecular mechanisms underlying air pollution neurotoxicity and its role in the development of AD/ADRD. These findings will provide key insights into the relationship between air pollution mixtures, biological response profiles, and ADRD, supporting future efforts that aim to inform environmental regulation and health policy to mitigate air pollution-related risk for AD/ADRD.
