Alzheimer's Disease, Genes, and Pesticide Use in the Agricultural Health Study

农业健康研究中的阿尔茨海默病、基因和农药使用

• 批准号: 9058063
• 负责人: BRENDA L PLASSMAN
• 金额: $ 53.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-13 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058063
• 关键词: Accounting; Address; Affect; Age; Aging; Agriculture; Algorithms; Alzheimer' s Disease; Alzheimer' s disease risk; Clinical; Cohort Studies; Consensus; Country; Data; Dementia; Environmental Exposure; Epidemiologic Studies; Equipment; Evaluation; Event; Exposure to; Frequencies; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Gold; Health; Hereditary Disease; High Prevalence; Home environment; Impaired cognition; Individual; Inflammation; Knowledge; Link; Longitudinal Studies; Metabolism; Methods; National Institute of Environmental Health Sciences; Neuraxis; Neurodegenerative Disorders; Organophosphates; Outcome; Participant; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pesticides; Population; Prospective Studies; Public Health; Research; Risk Factors; Science; Telephone; Testing; age related cognitive disorder; base; clinical Diagnosis; disability; experience; genetic analysis; high risk; modifiable risk; organochlorine exposure; pesticide exposure; population based; prevent; prolyl-proline; public health relevance; risk variant; sample collection; screening; toxic organophosphate insecticide exposure

DESCRIPTION (provided by applicant): Both environmental and genetic components contribute to Alzheimer's disease (AD), but there has been limited research determining a link between exposure, genetics, and AD. One ubiquitous environmental exposure is pesticides, which affect the central nervous system and are associated with increased risk of AD in some studies. Current understanding of the association between pesticide exposure and AD is limited by knowledge gaps due to prior studies lacking detailed information on pesticide exposure, reliance on retrospective recall of exposure years after pesticide use, and lack of control for genes known to contribute to AD risk. We propose to address existing knowledge gaps in pesticide-related risks for AD by combining a proven method to identify individuals with AD, genetic sample collection, and detailed information on pesticide exposure in the Agricultural Health Study (AHS). We propose to identify AD cases beginning with telephone dementia screening of 4000 AHS participants, combined with an in-home evaluation of suspected cases and selected controls, leading to a consensus clinical diagnosis of AD and other dementias. Our rationale for the AHS is that it is the best-suited population study for examining pesticide exposure outcomes because it collected detailed information on pesticide use during or near the period of exposure, rather than retrospective estimates obtained years after potential exposure. A critical advantage to the AHS assessment approach is that it provides more accurate information on specific pesticide compounds, use of protective equipment, and mixing methods, leading to more advanced algorithms for estimating exposure. Because the AHS is an established longitudinal study, its well-characterized data can facilitate a prospective study of dementia that would otherwise take decades to complete if established de novo. We will leverage our research group's extensive experience and proven methods for AD case identification and genetic analysis in population-based studies. The unique strengths of the AHS and the project team make the current proposal exceptionally well- suited to address critical scientific questions posed by the Research Funding Announcement (RFA-ES-13- 006). Our Specific Aims are to 1) examine whether AD is associated with levels of pesticide exposure and types of pesticide use among pesticide applicators in the AHS, 2) examine the association between levels of pesticide exposure and AD after accounting for known AD genes and inflammation genes, and 3) examine the association between levels of pesticide exposure and AD, stratifying by genes known to alter metabolism of pesticides. Knowledge gained from the proposed research can be used to identify modifiable risk factors for AD and to develop strategies to reduce AD risk due to environmental exposures.

描述（由申请人提供）：环境和遗传因素都有助于阿尔茨海默病（AD），但确定暴露、遗传和AD之间联系的研究有限。一种普遍存在的环境暴露是农药，它会影响中枢神经系统，并在一些研究中与AD风险增加有关。目前对农药暴露与AD之间关系的理解受到知识差距的限制，这是由于先前的研究缺乏农药暴露的详细信息，依赖于农药使用后几年的回顾性召回，以及缺乏对已知导致AD风险的基因的控制。我们建议通过结合一种经证实的方法来识别AD患者，遗传样本收集和农业健康研究（AHS）中农药暴露的详细信息，来解决AD农药相关风险的现有知识缺口。我们建议从4000名AHS参与者的电话痴呆筛查开始识别AD病例，并结合对疑似病例和选定对照的家庭评估，从而达成AD和其他痴呆的共识临床诊断。我们对AHS的理由是，它是检查农药暴露结果的最合适的人群研究，因为它收集了暴露期间或接近暴露期间农药使用的详细信息，而不是在潜在暴露后数年获得的回顾性估计。AHS评估方法的一个关键优势是，它提供了关于特定农药化合物、防护设备的使用和混合方法的更准确的信息，从而产生了更先进的估计接触的算法。由于AHS是一项既定的纵向研究，其良好的特征数据可以促进痴呆症的前瞻性研究，否则如果从头建立，需要数十年才能完成。我们将利用我们的研究小组的丰富经验和成熟的方法，在基于人群的研究中进行AD病例识别和遗传分析。AHS和项目团队的独特优势使目前的提案非常适合解决研究资助公告（RFA-ES-13- 006）提出的关键科学问题。我们的具体目标是1）检查AD是否与AHS中农药施用者的农药暴露水平和农药使用类型相关，2）在考虑已知AD基因和炎症基因后检查农药暴露水平与AD之间的关联，以及3）检查农药暴露水平与AD之间的关联，通过已知改变农药代谢的基因进行分层。从拟议的研究中获得的知识可用于识别AD的可改变的风险因素，并制定策略，以减少由于环境暴露导致的AD风险。