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

描述（由申请人提供）：10 - 25%的晚发性阿尔茨海默病（AD）患者表现出明显的执行能力缺陷。诸如正面变体AD、执行突出AD和非执行性AD等名称已被应用于这一现象。对于执行性AD的传统或遗传风险因素所知甚少。该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，以期最终开发出改变疾病的治疗方法。该项目将利用大规模全基因组基因型和序列数据，以及从19项合作研究中收集的17000名参与者的认知数据。研究人员将使用现代心理测量方法来共同校准认知数据，以在记忆和执行功能的同一度量标准上开发分数。研究人员将使用这些分数来确定他们发现的具有高度遗传性的连续执行障碍谱系表型，其遗传模式与AD完全不同。调查人员会

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.