Project 2: Genetic Contributions to AD in DS

项目 2：DS 中 AD 的遗传贡献

• 批准号: 10264843
• 负责人: Joseph Hyungwoo Lee
• 金额: $ 49.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264843
• 关键词: Address; Adult; Affect; Age; Age-Years; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Autopsy; Biological; Biological Assay; Biological Markers; Blood; Candidate Disease Gene; Chromosome 21; Clinical; Clinical Data; Clinical Trials; Collection; Communities; Data; Data Set; Dementia; Deposition; Development; Disease Pathway; Disease Progression; Down Syndrome; Epidemiology; Future; Gene Expression; General Population; Genes; Genetic; Genetic Diseases; Genomics; Genotype; Goals; Image; Imaging Techniques; Impaired cognition; Individual; Inherited; Late Onset Alzheimer Disease; Life Expectancy; Machine Learning; Magnetic Resonance Imaging; Mediating; Methods; Modeling; Molecular Profiling; Multiomic Data; Natural History; Nerve Degeneration; Neurofibrillary Tangles; Neuropsychology; Pathway interactions; Performance; Phenotype; Play; Population; Positron-Emission Tomography; Prefrontal Cortex; Proteomics; Public Health; Resistance; Risk; Role; Sampling; Senile Plaques; Severity of illness; Structure; Technology; Time; Tissue-Specific Gene Expression; Tissues; Variant; base; cerebrovascular pathology; clinical phenotype; clinical risk; clinical subtypes; cohort; data mining; dementia risk; design; endophenotype; extracellular; genetic variant; genome sequencing; genomic data; genomic locus; high risk; individual variation; insight; metabolomics; mild cognitive impairment; multiple omics; neuroimaging marker; neuroinflammation; neuropathology; non-genetic; non-invasive imaging; novel; overexpression; polygenic risk score; pre-clinical; precision medicine; predictive marker; protective factors; tau Proteins; transcriptomics; virtual; whole genome

PROJECT 2 ABSTRACT The overall goal of Project 2 is to identify and characterize genetic factors in Down syndrome (DS) that contribute to the individual variation observed in three states of key symptomatic cognitive decline – unaffected (preclinical), mild cognitive impairment (prodromal), and dementia – as characterized in Project 1. Project 2, in turn, will help to delineate clinical subtypes and their progression to establish an efficient and parsimonious set of biomarker profiles that can be applied to the practice of precision medicine, which is the main goal of Project 3. Virtually, all adults with DS develop Alzheimer's disease (AD)-associated neuropathology by 40 years of age, with the risk of AD increasing rapidly from the late 40s or the early 50s. Yet, there is a wide range of age at onset of AD and severity of AD, and some adults with DS do not develop AD even at older ages. As the life expectancy of individuals with DS is reaching 60s and beyond, AD in this cohort is becoming a public health problem. With recent advances in assays for blood- and CSF-based biomarkers along with non-invasive imaging techniques, our objective is to accurately assess the risk of dementia by defining the molecular signatures associated with the progression of dementia and identify risk and protective genetic factors and their pathways using state of the art technologies. This study may help to discover causal and protective factors in the general population. To accomplish the main goal of the study, we propose to leverage existing longitudinal biomarker, imaging, and clinical data to identify genomic, transcriptomic, proteomic, and metabolomic factors that influence the amyloid, tau and other neurodegenerative pathways that influence the development of AD in adults with DS. Specifically, we will: (1) identify genetic loci that are associated with symptomatic cognitive impairments, including mild cognitive impairment (MCI) and dementia in adults with DS; (2) further examine genetic loci that contribute to variation in AD-related endophenotypes, including blood- and CSF-derived multiomic biomarkers, neuroimaging markers, and clinical phenotypes; (3) replicate candidate genetic loci identified from the ABC-DS cohort in several external cohorts, including an independent cohort of DS adults (PI: Silverman), the high-risk Dominantly Inherited Alzheimer Network (DIAN) cohort and the Alzheimer's Disease Genetics Consortium (ADGC); and (4) perform integrative analysis using the genetic and non-genetic factors identified in Projects 2 and 1, respectively, to identify highly predictive biomarkers that can be used in clinical trials.

项目2摘要 项目2的总体目标是识别和表征唐氏综合症（DS）的遗传因素 在三个关键的症状认知下降状态下观察到的个体变异 - 不受影响（临床前）， 轻度认知障碍（前驱）和痴呆症 - 如项目1。项目2所述，反过来将有助于 描绘临床亚型及其进展，以建立有效且典型的生物标志物集 可以应用于精密医学实践的概况，这是项目3的主要目标。 实际上，所有患有DS的成年人发展了阿尔茨海默氏病（AD）与40岁的神经病理学相关， 从40年代末或50年代初开始，广告的风险迅速增加。然而，发病时期有很多年龄 AD和AD的严重程度以及某些具有DS的成年人即使在年龄较大的年龄也不会发展AD。作为预期寿命 在有DS的个人中，已达到60年代及以后，该队列中的广告正在成为一个公共卫生问题。和 基于血液和CSF的生物标志物的测定法以及非侵入性成像技术的最新进展， 我们的目标是通过定义与 痴呆症的进展，并使用状态 艺术技术。这项研究可能有助于发现普通人群中的因果因素和受保护因素。 为了实现研究的主要目标，我们建议利用现有的纵向生物标志物，成像和 临床数据以识别影响淀粉样蛋白的基因组，转录组，蛋白质组学和代谢组因子 TAU和其他影响DS成人AD发展的神经退行性途径。具体来说， 我们将：（1）确定与对称认知障碍相关的遗传位置， 在患有DS的成年人中包括轻度认知障碍（MCI）和痴呆症； （2）进一步检查遗传基因座 有助于广告相关的内型型的变化，包括血液和CSF衍生的多层生物标志物， 神经影像标记和临床表型； （3）复制从ABC-DS定位的候选遗传 在几个外部队列中的队列，包括独立的DS成人队列（PI：Silverman），高风险 主要继承的阿尔茨海默氏症网络（Dian）队列和阿尔茨海默氏病遗传学财团 （ADGC）; （4）使用项目2中确定的遗传和非遗传因素进行综合分析 和1分别识别可用于临床试验的高度预测性生物标志物。