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: 9297187
• 负责人: Paul K Crane
• 金额: $ 63.8万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297187
• 关键词: 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; Funding Mechanisms; Genes; Genetic; Genetic Variation; Genotype; Goals; Hereditary Disease; Heritability; Hypertension; Investigation; Knowledge; Late Onset Alzheimer Disease; Lead; Memory; Memory impairment; Methods; Modernization; Names; Neuropsychology; Nucleotides; Parents; Participant; Pathway Analysis; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Prospective cohort study; Psychometrics; Randomized; Religion and Spirituality; Research; Research Personnel; Risk; Risk Factors; Series; Time; Variant; Washington; Work; clinical epidemiology; disorder subtype; drug development; epidemiologic data; epidemiology study; executive function; exome; exome sequencing; family structure; genetic analysis; genetic epidemiology; genetic risk factor; genome sequencing; genome-wide; improved; longitudinal analysis; phenotypic data; public health relevance; whole genome

DESCRIPTION (provided by applicant): 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.

描述(由申请人提供)：10%至25%的晚发性阿尔茨海默病(AD)患者存在明显的执行缺陷。前额变异型AD、执行突出AD和执行困难AD等名称被用来描述这一现象。人们对AD的传统或遗传危险因素知之甚少。这个项目的总体目标是进一步了解AD的遗传结构和临床流行病学，以期最终开发出改善疾病的治疗方法。该项目将利用19项合作研究中对17,000名参与者收集的大规模全基因组的基因和序列数据以及认知数据。研究人员将使用现代心理测量学方法来共同校准认知数据，以在相同的记忆和执行功能指标上得出分数。研究人员将使用这些分数来确定他们发现的高度可遗传的持续执行障碍表型，其遗传性模式与AD完全不同。调查人员将 为AIM 1利用全基因组的基因数据。合作研究中有5项是前瞻性队列研究，拥有来自10,000名参与者的广泛认知和临床数据。研究人员将利用这些数据用于AIM 2。几种资助机制正在为AD患者产生全基因组和全外显子组测序数据。研究人员将利用这些数据用于AIM 3。总而言之，这些调查有望改善人们对高度可遗传和毁灭性的AD亚型--执行障碍AD的了解。这项工作可能会确定与AD风险相关的遗传基因，这反过来可能导致药物的开发，从而显著改善这种疾病患者的生活。