Genetic Architecture of Alzheimer’s disease Proteinopathies

阿尔茨海默病的遗传结构 蛋白质病

• 批准号: 10581599
• 负责人: Carlos Cruchaga
• 金额: $ 189.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581599
• 关键词: Acceleration; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Apolipoprotein E; Automobile Driving; Autopsy; Bioinformatics; Biological; Biological Markers; Brain; Brain Diseases; Cell model; Cell physiology; Cerebrospinal Fluid; Clinical; Data; Data Set; Dementia; Disease; Etiology; Gene Expression; Genes; Genetic; Genetic Variation; Genetic study; Genome Scan; Genomics; Genotype; Goals; Impaired cognition; In Vitro; Individual; Intervention; Magnetic Resonance Imaging; Measures; Mediation; Mendelian randomization; Methods; Myeloid Cells; National Institute on Aging; Nature; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Injury; Outcome; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Persons; Phase; Phenotype; Plasma; Positron-Emission Tomography; Preventive measure; Proxy; Public Health; Quantitative Trait Loci; Recommendation; Research; Research Subjects; Risk; Role; Sampling; Senile Plaques; Signal Transduction; Symptoms; Testing; Variant; abeta deposition; amyloid pathology; biomarker validation; clinical diagnosis; comorbidity; diagnostic value; effective therapy; endophenotype; experimental study; extracellular; fluorodeoxyglucose positron emission tomography; follow-up; genetic architecture; genetic association; genetic information; genetic variant; genome sequencing; genome wide association study; improved; interest; neuroimaging; neuropathology; novel; personalized medicine; polygenic risk score; population based; pre-clinical; prevent; rare variant; tau Proteins; tau-1; whole genome

Project Summary/Abstract In order to enhance and focus research on Alzheimer's disease (AD)-specific proteinopathies, the 2018 research framework proposed by the National Institute on Aging and Alzheimer's Association (NIA-AA) recommends that AD be defined by its specific biological signatures that can be documented at autopsy or in living people by biomarkers rather than by its non-specific neurodegenerative and clinical syndromic features. Of the three proposed biomarkers by the NIA-AA research framework in living people (amyloid-beta (Aβ), pathologic tau and neurodegeneration), only the two AD-specific proteinopathies (Aβ and pathologic tau) are considered obligatory for the biological definition of AD, while neurodegeneration, although contribute to cognitive impairment and is part of the fully manifested disease, can also occur in other brain disorders and thus is not specific to AD. The purpose of this harmonized biological definition of AD in living people that includes the preclinical phase is to distinguish AD from other types of brain disorders and dementia, to accelerate and focus research on AD-specific proteinopathies that manifest decades before the clinical manifestation of first symptoms of AD, to enhance better understanding in the underlying mechanisms of AD clinical expression, and to use (and discover) targeted disease modifying interventions that can prevent or delay the onset of AD symptoms. Our ongoing and long-term research interest coincides well with the NIA-AA research framework in living people where we have already performed genome-wide association studies (GWAS) on CSF Aβ42/tau levels and Aβ deposition in the brain measured by amyloid-PET and identified known and novel associations in the APOE and non-APOE regions. However, the identified signals do not explain all of the phenotypic variation in the two AD-specific proteinopathies or endophenotypes. Here we propose a collaborative study between leading experts in the field to extend our ongoing efforts to delineate the complete genetic basis of the two AD- specific proteinopathies (Aβ and pathologic tau) by whole genome sequencing (WGS) using well-characterized and large amyloid-PET and CSF Aβ42/tau datasets with clinical outcomes of dementia followed by testing the effects of identified significant variants on downstream neurodegeneration markers, and performing extensive bioinformatics and functional studies. The primary objective of this application is to perform and analyze WGS in adequately powered large discovery samples with well-characterized Aβ and tau data along with clinical outcomes of dementia to identify putative functional variants associated with Aβ and tau pathologies followed by replications in independent and large samples with Aβ and tau data (Aims 1-2). We will integrate genetic information to create polygenic risk scores in order to predict Aβ and tau pathologies and will also examine the role of AD pathology-associated variants with downstream neurodegeneration, neuropathologies that coexist with AD and the risk and age-at-onset of AD (Aim3). Finally, we will functionally characterize genetic association using bioinformatics, causality tests and in vitro experiments to understand their roles in affecting gene expression as being expression quantitative traits loci, affecting intracellular and extracellular APP/Aβ and tau levels, and in myeloid cell function. The successful completion of this study will help to identify novel AD-related genes and pathways, and to uncover underlying possible mechanisms for AD.

项目摘要/摘要 为了增强和重点研究阿尔茨海默氏病（AD）特定蛋白质，2018年 美国国家老化研究所和阿尔茨海默氏症协会（NIA-AA）提出的研究框架 建议通过其特定的生物学特征来定义广告，该特定的生物学特征可以记录在尸检时或IN 生物标志物而不是其非特异性神经退行性和临床综合征特征。 NIA-AA研究框架的三种拟议的生物标志物（淀粉样蛋白β（Aβ）， 病理性的tau和神经退行性），仅两种AD特异性蛋白质病（Aβ和病理tau）是 被认为是AD的生物学定义的强制性，而神经退行性则有助于 认知障碍，是完全明显疾病的一部分，也可能发生在其他脑部疾病中 因此不是特定于AD的。这个在活人中对广告的统一生物学定义的目的 包括临床前阶段是将AD与其他类型的脑疾病和痴呆区分开， 加速并重点研究广告特异性的蛋白质病，这些蛋白质疾病在临床之前几十年表现出来 AD的首次症状的表现，以增强在AD的潜在机制中更好地理解 临床表达，并使用（并发现）有针对性的疾病修改可以预防或 延迟广告符号的发作。 我们正在进行的长期研究兴趣与NIA-AA生活框架相吻合 我们已经在CSFAβ42/TAU水平上进行了全基因组关联研究（GWAS）的人 通过淀粉样-PET测量的大脑中的Aβ沉积，并确定了已知和新颖的关联 APOE和非APOE地区。但是，已确定的信号并不能解释所有表型变化 两种AD特异性蛋白质病或内表型。在这里，我们提出了一项合作研究 该领域的领先专家扩大了我们持续的努力来描述这两个广告的完整遗传基础 通过良好的特征化，整个基因组测序（WGS）的特定蛋白质病（Aβ和病理TAU） 以及具有痴呆症的临床结局，然后测试大型淀粉样蛋白PET和CSFAβ42/TAU数据集 鉴定出明显变体对下游神经变性标记的影响，并进行广泛的影响 生物信息学和功能研究。该应用的主要目的是执行和分析WGS 在充分动力的大型发现样品中，具有良好的Aβ和TAU数据以及临床 痴呆症的结果以识别与Aβ和TAU病理相关的推定功能变异 通过在具有Aβ和TAU数据的独立和大型样品中复制（目标1-2）。我们将整合遗传 信息以创建多基因风险评分以预测Aβ和TAU病理，还将检查 与下游神经退行性变体相关变体的作用，神经病理学 AD以及AD的风险和年龄（AIM3）。最后，我们将在功能上表征通用 使用生物信息学，休闲测试和体外实验的关联，以了解其影响 基因表达是表达定量性状基因座，影响细胞内和细胞外应用/Aβ 和tau水平，以及髓样细胞功能。这项研究的成功完成将有助于确定新颖 与广告相关的基因和途径，并发现AD的潜在机制。