Air Pollution, Metabolome, and Alzheimer disease in Mexican Americans

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PROJECT ABSTRACT Air pollution is increasingly recognized as an important risk factor for cognitive impairment (CI) and Alzheimer’s and related dementias (ADRD). To gain insights into the biologic processes which link air pollution exposure and ADRD in humans during aging, we propose an integrative longitudinal metabolomics approach in a large population-based cohort of Mexican-Americans relying on real-life, long-term air pollution exposures for which we established links with ADRD. Metabolomics can provide a map of exposure and disease-related perturbations across interconnected biological pathways. It is especially useful in gaining understanding of disease processes when repeated biosamples are available before diagnosis to provide novel information about initiation and progression of cognitive impairment and ADRD. Specifically, we propose to use untargeted and targeted metabolomics to further mechanistic understanding of long-term exposures to air pollution and CI/ADRD in an elderly population of Mexican Americans from the “Sacramento Area Latino Study on Aging” (SALSA), taking advantage of 5689 existing blood samples from 1,789 Latino participants followed over 10 years, screened for cognitive function (7,696 repeated cognitive exams), and tested with multi-domain neuro-psychological batteries, clinical and MRI assessments for dementia adjudication. Latino minority populations suffer disparities in exposures and a high prevalence of comorbid risk factors, such as diabetes. We have already observed strong associations for air pollution exposure with incident ADRD. Previously, we conducted an air monitoring campaign and combined this with routine monitoring data, land use, emissions, traffic data, and meteorology to generate air pollution exposures for SALSA participants (R01ES023451 mPIs: Ritz/Haan). Here, we will collaborate with Dr. Jones at Emory who directs a Center that developed cutting edge high-performance metabolic profiling methods. We will employ these unique resources to identify molecular mechanisms of air pollution and CI/ADRD in Latinos longitudinally, to show how the metabolome is changing as cognition declines and CI/ADRD develops, how air pollution exposure changes the metabolome over follow-up, and how vulnerability or resilience contributes to the process of developing dementia. We will also evaluate the influence of air pollution on intermediate biomarkers previously linked to CI/ADRD, including inflammatory, metabolic, and antioxidant markers (TNF-a, IL6, CRP etc.). Finally, we will study how known ADRD risk factors such as APOE4, diabetes, physical activity, or gender affect air pollution related metabolomic profiles using repeated measures and multi- level clustering to generate insight into the multifactorial etiologies of CI/ADRD. We also propose to conduct replication analyses using existing metabolomics from the same platform, air pollution and cognitive assessment data in 277 elderly Central Californians. This study will improve our understanding of mechanisms of air pollution toxicity related to CI/ADRD, such pathways may provide actionable and treatable targets. It will also help find evidence-based biomarkers for those most at risk and support causality and suggest mitigation approaches.