Genetic architecture of memory and executive functioning in Alzheimer's disease

阿尔茨海默病记忆和执行功能的遗传结构

• 批准号: 8630958
• 负责人: Paul K Crane
• 金额: $ 76.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630958
• 关键词: Abbreviations; Accounting; Adult; Aging; Alzheimer' s Disease; Architecture; Candidate Disease Gene; Clinical; Clinical Data; Cognition; Cognitive; Cohort Studies; Data; Data Set; Detection; Development; Diabetes Mellitus; Diagnosis; Disease; Elderly; Epidemiology; Executive Dysfunction; Funding Mechanisms; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Height; Heritability; Hypertension; Investigation; Knowledge; Late Onset Alzheimer Disease; Lead; Memory; Methods; Metric; Names; Nucleotides; Parents; Participant; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Prospective Studies; Psychometrics; Randomized; Relative (related person); Religion and Spirituality; Research; Research Personnel; Risk; Risk Factors; Series; Text; Time; Variant; Washington; Work; clinical epidemiology; disorder subtype; drug development; executive function; exome; exome sequencing; family structure; genetic analysis; genetic risk factor; genome sequencing; genome-wide; improved; neuropsychological; prospective; public health relevance; spelling

Ten to 25% of people with late-onset Alzheimer's disease (AD) present with prominent executive deficits. Names such as frontal variant AD, executive prominent AD, and dysexecutive AD have been applied to this phenomenon. Little is known about traditional or genetic risk factors for dysexecutive AD. The overarching goal of this project is to further our understanding of the genetic architecture and clinical epidemiology of dysexecutive AD in the hopes of ultimately developing disease- modifying treatments. This project will leverage large-scale genome-wide genotype and sequence data and cognitive data collected on >17,000 participants across 19 collaborating studies. The investigators will use modern psychometric methods to co-calibrate cognitive data to develop scores on the same metric for memory and executive functioning. The investigators will use these scores to determine a continuous dysexecutive spectrum phenotype they have found to be highly heritable, with a pattern of heritability entirely distinct from that of AD. The investigators will leverage genome-wide genotype data for Aim 1. Five of the collaborating studies are prospective cohort studies with extensive cognitive and clinical data from >10,000 participants. The investigators will leverage these data for Aim 2. Several funding mechanisms are producing whole genome and whole exome sequencing data for people with AD. The investigators will leverage these data for Aim 3. Taken together, these investigations promise to improve what is known about dysexecutive AD, a highly heritable and devastating AD subtype. This work may identify genetic loci associated with risk for dysexecutive AD, which in turn may lead to development of drugs that could dramatically improve the lives of people with this condition.

10%至25%的晚发性阿尔茨海默病（AD）患者存在显著的 行政赤字。诸如额叶变体AD、执行突出AD和 dysexecutive AD已经应用于这种现象。知之甚少 传统的或遗传的风险因素。这个项目的首要目标是 该项目旨在进一步了解遗传结构和临床 执行障碍性AD的流行病学，希望最终发展成疾病， 修改治疗。 该项目将利用大规模的全基因组基因型和序列数据， 在19项合作研究中收集了超过17，000名参与者的认知数据。的 研究人员将使用现代心理测量方法来共同校准认知数据， 在记忆力和执行功能上建立相同的分数。的 研究人员将使用这些分数来确定持续的执行障碍谱 他们发现，表型是高度遗传的，具有完全遗传的模式， 与AD不同。研究人员将利用全基因组基因型数据， 目标1。五项合作研究是前瞻性队列研究， 来自> 10，000名参与者的认知和临床数据。调查人员会利用 目标2的数据。几个供资机制正在生产全基因组， AD患者的全外显子组测序数据。调查人员将利用这些 目标3的数据 总的来说，这些调查有望改善我们对 执行障碍性AD是一种高度遗传和破坏性的AD亚型。这项工作可以识别 与执行障碍AD风险相关的遗传位点，这反过来可能导致 开发药物，可以大大改善人们的生活， 条件