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

描述(由申请人提供)：环境和遗传因素都会导致阿尔茨海默病(AD)，但确定暴露、遗传和AD之间的联系的研究有限。一种普遍存在的环境暴露是杀虫剂，它会影响中枢神经系统，在一些研究中与AD风险增加有关。目前对农药暴露与阿尔茨海默病之间的联系的了解受到知识差距的限制，这是因为以前的研究缺乏关于农药暴露的详细信息，依赖于在使用农药后多年对暴露的回顾，以及对已知的导致AD风险的基因缺乏控制。我们建议通过结合农业健康研究(AHS)中已证实的识别AD个体的方法、遗传样本收集和农药暴露的详细信息来解决与农药相关的AD风险的现有知识差距。我们建议从对4000名AHS参与者进行电话痴呆症筛查开始，结合对疑似病例和选定的对照进行家庭评估，识别AD病例，导致对AD和其他痴呆的临床诊断达成共识。我们支持AHS的理由是，这是检验农药暴露结果的最合适的人群研究，因为它收集了在暴露期间或接近暴露期间使用杀虫剂的详细信息，而不是在潜在暴露数年后获得的追溯估计。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、保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暴露的算法。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对痴呆症的前瞻性研究，否则如果建立从头开始，将需要数十年的时间才能完成。我们将利用我们研究小组的丰富经验和成熟的方法，在以人群为基础的研究中识别AD病例和进行基因分析。AHS和项目团队的独特优势使目前的提案非常适合于解决研究资助公告(RFA-ES-13-006)提出的关键科学问题。我们的具体目标是：1)检查AHS中农药施用者的农药暴露水平和农药使用类型是否与AD有关；2)在考虑已知的AD基因和炎症基因后，检查农药暴露水平与AD之间的联系；3)检查农药暴露水平与AD之间的关系，按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以用来确定AD的可改变的风险因素，并制定策略来减少由于环境暴露而造成的AD风险。

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.