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

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。诸如额叶变异型AD、执行突出型AD和执行障碍型AD等名称已被应用于这种现象。很少有人知道的传统或遗传的风险因素为dysexecutive AD。该项目的总体目标是进一步了解执行障碍性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项合作研究中收集的超过17，000名参与者的大规模全基因组基因型和序列数据以及认知数据。研究人员将使用现代心理测量方法来共同校准认知数据，以制定记忆和执行功能相同指标的分数。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表型，其遗传性模式完全不同于AD。调查人员将 利用Aim 1的全基因组基因型数据。其中五项合作研究是前瞻性队列研究，具有来自> 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实现目标2。一些资助机制正在为AD患者提供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实现目标3。总的来说，这些研究有望改善对执行障碍AD的了解，这是一种高度遗传和破坏性的AD亚型。这项工作可能会确定与执行障碍AD风险相关的遗传位点，这反过来可能会导致药物的开发，从而大大改善患有这种疾病的人的生活。

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.