Environmental Moderation of Genetic Influences on Dementia Risk in Mexican Older Adults

项目总结/摘要 墨西哥老年人预计将面临不成比例的阿尔茨海默病和相关痴呆症 （ADRD）[1]，但解释这些ADRD差异的潜在环境和遗传因素是 没有完全理解。针对这些差异提出的一种机制是累积劣势理论， 其中在整个生命过程中对不同遗传或环境风险因素的不同暴露 导致ADRD患病率升高[2-4]。然而，系统地 测试这一理论是否解释了观察到的差异，由于缺乏对以下问题的研究而受到阻碍： 遗传和社会环境ADRD危险因素在墨西哥老年人。拟定的研究将 阐明墨西哥老年人ADRD基因表达最大化的环境条件 并最小化。首先，我将详细说明多种环境因素的影响（即，教育，识字， 社会经济地位，农村和移民）对ADRD风险。第二，我将测试每一个的修改作用， 环境因素对载脂蛋白E（APOE）对ADRD风险的影响。第三，我将测试的修改作用， 每个环境因素对ADRD的多基因风险评分（PRS）的影响， 墨西哥血统对ADRD风险的影响。到目前为止，还没有研究检查基因与环境的风险因素， 墨西哥老年人的ADRD风险拟议的研究将利用大规模的社区数据集， 墨西哥健康和老龄化研究（MHAS;墨西哥），墨西哥原产PRS的样本已被 开发拟议的培训和研究计划涉及以下研究问题： 环境风险因素导致墨西哥老年人ADRD风险？环境保护在多大程度上 墨西哥老年人中常见ADRD遗传风险变异的风险因素中度影响？解决这些 问题，将解决以下具体目标：1）测试环境因素是否影响 通过潜在痴呆指数（LDI）在墨西哥老年人中进行ADRD风险评分; 2）测试环境是否 因素中度APOE ε4对墨西哥成年人LDI评分的影响; 3）测试环境因素是否 中度墨西哥裔PRS对墨西哥老年人LDI评分的影响。拟议的项目将是 这是第一项阐明ADRD风险升高的遗传和环境影响的研究 墨西哥老年人。提高对这些因素作用的认识， 对公共卫生的影响，因为这项研究将提供经验证据，以告知和制定有针对性的 可能减轻墨西哥老年人ADRD风险的干预策略。

PROJECT SUMMARY/ABSTRACT Mexican older adults are projected to face disproportionate rates of Alzheimer's disease and related dementias (ADRD) [1], but the underlying environmental and genetic factors accounting for these ADRD disparities are not fully understood. A proposed mechanism for these disparities is the cumulative disadvantage theory, wherein differential exposure to different genetic or environmental risk factors across the life course accumulate in ways that contribute to greater prevalence of ADRD [2-4]. However, the ability to systematically test whether this theory accounts for the observed disparities has been hindered by a lack of research on genetic and social environmental ADRD risk factors among Mexican older adults. The proposed study will clarify environmental conditions under which genetic expression of ADRD in Mexican older adults is maximized and minimized. First, I will specify effects of multiple environmental factors (i.e., education, literacy, socioeconomic status, rurality, and migration) on ADRD risk. Second, I will test the modifying role of each environmental factor on effects of apolipoprotein-E (APOE) on ADRD risk. Third, I will test the modifying role of each environmental factor on effects a polygenic risk score (PRS) for ADRD developed specifically in persons of Mexican ancestry on ADRD risk. No research to date has examined gene-by-environmental risk factors for ADRD risk in Mexican older adults. The proposed study will leverage a large-scale community-based dataset, the Mexican Health and Aging Study (MHAS; Mexico), the sample in which the Mexican origin PRS has been developed. The proposed training and research plan address the following research questions: Which environmental risk factors contribute to ADRD risk in Mexican older adults? To what extent do environmental risk factors moderate effects of common ADRD genetic risk variants in Mexican older adults? To address these questions, the following specific aims will be addressed: 1) Test whether the environmental factors influence ADRD risk scores in Mexican older adults via a latent dementia index (LDI); 2) Test whether environmental factors moderate APOE ε4 effects on LDI scores in Mexican adults; 3) Test whether environmental factors moderate the Mexican origin PRS effects on LDI scores in Mexican older adults. The proposed project will be the first study to elucidate the genetic and environmental influences that may underlie the elevated ADRD risk in Mexican older adults. Improved understanding of the role of these factors will also have important implications for public health, as this study will provide empirical evidence to inform and develop targeted intervention strategies that may mitigate ADRD risk among Mexican older adults.