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% 到 25% 的晚发性阿尔茨海默病 (AD) 患者会出现明显的症状 行政赤字。诸如额叶变体 AD、执行突出 AD 等名称 执行不良AD已应用于这种现象。鲜为人知的是 执行障碍性 AD 的传统或遗传风险因素。本次活动的总体目标是 该项目是为了进一步了解遗传结构和临床 执行障碍性 AD 的流行病学，希望最终发展为疾病 修改治疗方法。 该项目将利用大规模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。这 研究人员将使用现代心理测量方法来共同校准认知数据 根据记忆力和执行功能的同一指标制定分数。这 研究人员将使用这些分数来确定连续的执行不良谱 他们发现表型具有高度遗传性，具有完全遗传性的模式 与AD不同。研究人员将利用全基因组基因型数据 目标 1. 其中五项合作研究是前瞻性队列研究，具有广泛的研究 来自超过 10,000 名参与者的认知和临床数据。调查人员将利用 这些数据用于目标 2。一些资助机制正在产生全基因组和 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。 总而言之，这些调查有望改善已知的情况 执行障碍性 AD，一种高度遗传性和破坏性的 AD 亚型。这项工作可能会识别 与执行不良 AD 风险相关的遗传位点，这反过来又可能导致 开发可以显着改善患有这种疾病的人的生活的药物 健康）状况。