LEAD-GENE INTERACTIONS AND CONGNITION

描述：（由申请人提供）随着年龄的增长，认知能力下降是一种常见的现象，但并非不可避免。虽然目前许多研究都是针对阿尔茨海默病——认知能力下降最严重的表现之一——但目前针对识别与早期（即亚临床）认知能力下降相关的风险因素和机制的工作相对较少，尽管这可能是最容易预防的阶段。关于认知能力下降的病因学，需要澄清的一个重要问题是环境铅暴露的作用以及铅与特定候选基因的相互作用。在本应用中，我们讨论了四种候选基因——APOE、HFE（血色素沉着症）基因、转铁蛋白和Tau蛋白——如何与铅负荷相互作用，从而增加氧化细胞损伤的风险，从而导致神经元细胞损失和认知缺陷。我们回顾了过去11年我们对低水平铅毒性的研究，并描述了令人信服的初步数据。然后，我们提出了一项新的研究，要求在我们已建立的波士顿地区队列中收集新的数据[规范老龄化研究（NAS），护士健康研究（NHS）和社区领导研究（CLS）]。我们的具体目的是测试有关铅负荷认知影响的假设及其与我们感兴趣的四种多态性的潜在相互作用。我们将使用经过验证的一系列电话认知功能评估工具，以及自1993年以来我们一直亲自进行的一系列面对面的认知测试，从横截面和纵向上研究认知。这项研究的结果有望进一步阐明铅对社会的潜在影响，也可能产生识别易感个体以及早期大脑影响的工具。

DESCRIPTION: (provided by applicant) Cognitive decline is a common, but not inevitable, accompaniment to aging. While much research is currently being directed at Alzheimer' s Disease -- one of the most severe expressions of cognitive decline -- relatively little work is currently aimed at identifying risk factors and mechanisms associated with early (i.e., subclinical) cognitive decline, even though this may be the stage most amenable to prevention. An important issue that needs to be clarified in relation to the etiology of cognitive decline is the role of environmental lead exposure and the interaction of lead with specific candidate genes. In this application we discuss how four candidate genes -- APOE, the HFE (hemochromatosis) gene, transferrin, and Tau protein -- may interact with lead burden to increase the risk for oxidative cell damage leading to neuronal cell loss and cognitive deficits. We review the last 11 years of our research on low-level lead toxicity and describe compelling preliminary data. We then propose a new study that calls for new data collection in our established Bostonarea cohorts [Normative Aging Study (NAS), Nurses Health Study (NHS), and Community Lead Study (CLS)]. Our specific aims are to test hypotheses related to the impact on cognition of lead burden and its potential interaction with our four polymorphisms of interest. We will look at cognition cross-sectionally and longitudinally, using a validated battery of telephone cognitive function assessment tools as well as a battery of in-person cognitive tests that we have been administering in person since 1993. Results of this research promise to shed further light on lead's potential impact on society and may also give rise to tools for identifying susceptible individuals as well as early brain effects.