Air Pollution, Metabolome, and Alzheimer disease in Mexican Americans

项目摘要 空气污染越来越被认为是认知障碍（CI）和阿尔茨海默氏症的重要危险因素 和相关痴呆症（ADRD）。深入了解将空气污染暴露与 ADRD在人类衰老过程中，我们提出了一个整合的纵向代谢组学方法，在一个大的 墨西哥裔美国人的基于人口的队列，依赖于现实生活中的长期空气污染暴露， 我们与民主与发展联盟建立了联系。代谢组学可以提供暴露和疾病相关扰动的图谱 相互连接的生物学途径。它对了解疾病过程特别有用 当在诊断前可获得重复的生物样本以提供关于开始的新信息时， 认知障碍和ADRD的进展。具体而言，我们建议使用非目标性和目标性 代谢组学，以进一步了解长期暴露于空气污染和CI/ADRD的机制， 来自“萨克拉门托地区拉丁裔老龄化研究”（SALSA）的墨西哥裔美国人老年人口， 来自1，789名拉丁裔参与者的5689份现有血液样本的优势，随访10年以上， 认知功能（7，696次重复认知测试），并使用多领域神经心理电池进行测试， 用于痴呆判定的临床和MRI评估。拉丁裔少数民族人口在以下方面存在差异： 暴露和高患病率的共病风险因素，如糖尿病。我们已经观察到强 空气污染暴露与ADRD事件的关联。此前，我们开展了一项空气监测活动， 并将其与常规监测数据、土地使用、排放、交通数据和气象数据相结合， SALSA参与者的空气污染暴露（R 01 ES 023451 mPI：Ritz/哈安）。在这里，我们将与 博士琼斯在埃默里大学，他领导的一个中心开发了尖端的高性能代谢分析 方法.我们将利用这些独特的资源来确定空气污染和CI/ADRD的分子机制 在拉丁美洲人中，为了显示代谢组如何随着认知能力下降和CI/ADRD的发展而变化， 空气污染暴露如何改变后续代谢组，以及脆弱性或弹性如何 会导致痴呆症我们亦会评估空气污染对 先前与CI/ADRD相关的中间生物标志物，包括炎症、代谢和抗氧化剂 标志物（TNF-α、IL 6、CRP等）。最后，我们将研究已知的ADRD风险因素，如APOE 4，糖尿病， 身体活动或性别影响空气污染相关的代谢谱使用重复测量和多 水平聚类，以深入了解CI/ADRD的多因素病因。我们还建议进行 使用来自同一平台的现有代谢组学、空气污染和认知评估进行复制分析 277名加州中部老年人的数据。这项研究将提高我们对空气污染机理的认识 与CI/ADRD相关的毒性，这样的途径可以提供可操作和可治疗的靶标。这也将有助于找到 基于证据的生物标志物，为那些最危险的，支持因果关系，并建议缓解方法。

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.