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: 10391426
• 负责人: Carlos Cruchaga
• 金额: $ 210.2万
• 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/10391426
• 关键词: 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; Research; Research Subjects; Risk; Role; Sampling; Senile Plaques; Signal Transduction; Symptoms; Syndrome; Testing; Variant; abeta deposition; amyloid pathology; base; case control; 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.

项目概要/摘要 为了加强和集中对阿尔茨海默病 (AD) 特异性蛋白病的研究，2018 年 美国国家老龄化和阿尔茨海默病协会 (NIA-AA) 提出的研究框架 建议通过其特定的生物特征来定义 AD，这些特征可以在尸检或尸检中记录下来。 活人通过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 研究框架在活人中提出的三个生物标志物（β 淀粉样蛋白 (Aβ)、 病理性 tau 蛋白和神经变性），只有两种 AD 特异性蛋白病（Aβ 和病理性 tau 蛋白）是 被认为是 AD 的生物学定义所必需的，而神经变性虽然有助于 认知障碍是完全表现出来的疾病的一部分，也可能发生在其他脑部疾病和 因此并不是 AD 所特有的。对活人中的 AD 进行统一的生物学定义的目的是 包括临床前阶段的目的是将 AD 与其他类型的脑部疾病和痴呆症区分开来， 加速并重点研究 AD 特异性蛋白病，这些蛋白病在临床出现前数十年就已显现 AD 首发症状的表现，以加深对 AD 潜在机制的更好理解 临床表达，并使用（和发现）有针对性的疾病改变干预措施，可以预防或 延缓 AD 症状的出现。 我们正在进行的长期研究兴趣与 NIA-AA 在生活领域的研究框架非常吻合 我们已经对 CSF Aβ42/tau 水平进行了全基因组关联研究 (GWAS) 的人群 通过淀粉样蛋白 PET 测量大脑中的 Aβ 沉积，并确定了已知和新的关联 APOE 和非 APOE 区域。然而，所识别的信号并不能解释所有的表型变异 两种 AD 特异性蛋白质病或内表型。在这里，我们提出一项合作研究 该领域的领先专家将继续努力，描绘出这两种AD-的完整遗传基础 通过全基因组测序 (WGS) 使用充分表征的特定蛋白质病（Aβ 和病理性 tau） 以及大型淀粉样蛋白-PET 和 CSF Aβ42/tau 数据集，其中包含痴呆症的临床结果，然后测试 已识别的显着变异对下游神经变性标记物的影响，并进行广泛的研究 生物信息学和功能研究。该应用程序的主要目标是执行和分析 WGS 在具有充分表征的 Aβ 和 tau 数据以及临床数据的充足动力的大型发现样本中 痴呆症的结果以确定与 Aβ 和 tau 病理相关的推定功能变异 通过使用 Aβ 和 tau 数据在独立的大样本中进行复制（目标 1-2）。我们将整合基因 创建多基因风险评分的信息，以预测 Aβ 和 tau 病理，还将检查 AD 病理相关变异与下游神经变性、共存神经病理的作用 AD 以及 AD 的风险和发病年龄（目标 3）。最后，我们将从功能上表征遗传 使用生物信息学、因果关系测试和体外实验来了解它们在影响中的作用 基因表达作为表达数量性状位点，影响细胞内和细胞外 APP/Aβ 和 tau 水平以及骨髓细胞功能。这项研究的成功完成将有助于确定新颖的 AD 相关基因和通路，并揭示 AD 潜在的可能机制。