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之间联系的研究有限。一种无处不在的环境暴露是农药，它会影响中枢神经系统，在一些研究中与阿尔茨海默病的风险增加有关。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，目前对农药暴露与AD之间关系的理解受到知识空白的限制。我们建议通过结合一种成熟的识别AD个体的方法、基因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现有的关于AD农药相关风险的知识空白。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，从而得出AD和其他痴呆的共识临床诊断。我们进行AHS的理由是，它是最适合用于检查农药暴露结果的人群研究，因为它收集了在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暴露的算法。由于AHS是一项既定的纵向研究，其特征明确的数据可以促进对痴呆症的前瞻性研究，否则如果重新建立，则需要数十年才能完成。我们将利用我们研究小组的丰富经验和经过验证的方法，在基于人群的研究中进行阿尔茨海默病病例鉴定和基因分析。AHS和项目团队的独特优势使当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)研究AD是否与农药暴露水平和AHS中农药施药者的农药使用类型有关；2)在考虑已知的AD基因和炎症基因后，研究农药暴露水平与AD之间的关系；3)通过已知的改变农药代谢的基因进行分层，研究农药暴露水平与AD之间的关系。从拟议的研究中获得的知识可用于确定阿尔茨海默病的可改变风险因素，并制定减少因环境暴露而导致的阿尔茨海默病风险的策略。

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.