Genes, environments, interactions, and cognitive decline in the HRS

HRS 中的基因、环境、相互作用和认知能力下降

• 批准号: 8631800
• 负责人: Kathleen M Hayden
• 金额: $ 28.97万
• 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: 2014-09-30 至 2015-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631800
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Brain-Derived Neurotrophic Factor; CASP1 gene; Cognition; Cognitive; Complex; Coupled; Data; Development; Disease; Education; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiology; Episodic memory; Functional disorder; Gene Combinations; Genes; Genetic; Genetic Epistasis; Genotype; Health; Homeostasis; Impaired cognition; Impairment; Income; Individual; Inflammation; Inflammatory; Inherited; Interferons; Interleukin-10; Interleukin-6; Intervention; Late Onset Alzheimer Disease; Longitudinal Studies; MTHFR gene; Measures; Mental Depression; Methods; Metric; Modeling; Modification; Neighborhoods; Outcome; Participant; Pathway interactions; Pattern; Phase; Phenotype; Poverty; Prevalence; Prevention strategy; Public Assistance; Retirement; Risk; Role; Sampling; Socioeconomic Status; Stress; Telephone Interviews; Testing; Time; Unemployment; base; cardiovascular disorder risk; cardiovascular risk factor; cognitive function; disorder prevention; effective therapy; environmental stressor; follow-up; forest; gene environment interaction; gene interaction; genetic epidemiology; genetic risk factor; genome wide association study; inflammatory marker; interest; low socioeconomic status; neuropathology; performance tests; pre-clinical; risk variant; time use; trait

DESCRIPTION (provided by applicant): Genes, environments, interactions, and cognitive decline in the HRS Project Summary: Alzheimer's disease (AD) is a heterogeneous disease with a potentially wide range of contributing environmental and genetic risk factors. A long pre-clinical period of cognitive decline accompanies the accumulation of neuropathology and precedes the onset of AD. Navigating the many pathways to cognitive decline and dysfunction requires a multifaceted approach that incorporates both epidemiology and genetics. The role of epidemiology is crucial for identifying modifiable factors that may reduce AD risk; the role of genetics in AD has proven to be very complex. Early studies identified genes in the inflammatory pathways and genes associated with stress. Although some of these genes have shown evidence of environmental interactions, few have been investigated for interactions in AD and few have been replicated in genome wide association studies (GWAS). Instead, GWAS have yielded risk genes with relatively small effects, many of which have been tied to cognitive decline as well as AD. We propose to study interactions between AD risk genes, genes from the inflammatory pathway, environmental risk factors, and their combined influence on cognitive decline. Such interactions could explain a portion of AD prevalence that is currently unexplained. The Health and Retirement Study (HRS) longitudinal data coupled with newly released GWA data from over 11,000 participants age 65 and older provides an ideal opportunity to study these associations in a powerful way. Using latent trajectory models, we will define groups of individuals based on cognitive test performance over time. Using random forests, we will study the associations between cognitive trajectories and AD risk genes, inflammation genes, environmental factors, and their interactions. This approach, combining complex methods, will allow us to study in greater detail the interrelationships between genes, environments, and their interactions as they influence the rate of cognitive decline.

描述（由申请人提供）：HRS 项目中的基因、环境、相互作用和认知能力下降 摘要：阿尔茨海默病 (AD) 是一种异质性疾病，具有多种潜在的环境和遗传风险因素。在 AD 发病之前，伴随着神经病理学的积累，会出现一段漫长的临床前认知衰退期。解决认知能力下降和功能障碍的多种途径需要采取多方面的方法，将流行病学和遗传学结合起来。流行病学对于识别可降低 AD 风险的可改变因素至关重要；事实证明，遗传学在 AD 中的作用非常复杂。早期研究发现了炎症途径中的基因和与压力相关的基因。尽管其中一些基因已显示出与环境相互作用的证据，但很少有人研究过 AD 中的相互作用，也很少在全基因组关联研究 (GWAS) 中得到复制。相反，GWAS 产生了影响相对较小的风险基因，其中许多与认知能力下降和 AD 相关。我们建议研究 AD 风险基因、炎症途径基因、环境风险因素之间的相互作用，以及它们对认知能力下降的综合影响。这种相互作用可以解释部分目前无法解释的 AD 患病率。健康与退休研究 (HRS) 纵向数据与来自超过 11,000 名 65 岁及以上参与者的新发布的 GWA 数据相结合，为有效研究这些关联提供了理想的机会。使用潜在轨迹模型，我们将根据一段时间内的认知测试表现来定义个体群体。使用随机森林，我们将研究认知轨迹与 AD 风险基因、炎症基因、环境因素及其相互作用之间的关联。这种方法结合了复杂的方法，将使我们能够更详细地研究基因、环境及其相互作用之间的相互关系，因为它们影响认知能力下降的速度。