Genetic Architecture of Alzheimer’s disease Proteinopathies

项目总结/摘要 为了加强和关注阿尔茨海默病（AD）特异性蛋白质病的研究，2018年 国家老龄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AD通过其特定的生物学特征来定义，这些特征可以在尸检时记录下来， 生物标志物，而不是其非特异性神经退行性和临床综合征的特点。 在NIA-AA研究框架在活人中提出的三种生物标志物（淀粉样蛋白β（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） 被认为是AD生物学定义的必要条件，而神经退行性疾病，虽然有助于 认知障碍是完全表现的疾病的一部分，也可能发生在其他大脑疾病中， 因此不是AD所特有的。这种在活人中对AD的统一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， 加速并专注于AD特异性蛋白质病的研究，这些蛋白质病在临床治疗前几十年就已表现出来。 AD首发症状的表现，以提高对AD潜在机制的更好理解 临床表达，并使用（和发现）有针对性的疾病修饰干预措施，可以预防或 延缓AD症状的发作。 我们正在进行的和长期的研究兴趣与NIA-AA的生活研究框架不谋而合。 我们已经对CSF Aβ42/tau水平进行了全基因组关联研究（GWAS）的患者 和Aβ沉积，并确定了已知的和新的关联， APOE和非APOE区域。然而，鉴定的信号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，我们提出了一个合作研究之间 该领域的领先专家，以扩大我们正在进行的努力，以划定完整的遗传基础，两个广告- 使用充分表征的全基因组测序（WGS）， 和大的淀粉样蛋白PET和CSF Aβ42/tau数据集与痴呆的临床结局，然后测试 鉴定的显著变体对下游神经变性标志物的影响，并进行广泛的 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数据沿着临床 痴呆的结果，以确定与Aβ和tau病理学相关的推定功能变体， 通过在具有Aβ和tau数据的独立和大样本中进行重复（目的1-2）。我们将整合基因 信息来创建多基因风险评分，以预测Aβ和tau病理，并将检查 AD病理相关变异与下游神经变性、共存的神经病理的作用 与AD和AD的风险和发病年龄（Aim 3）。最后，我们将从功能上描述遗传 使用生物信息学，因果关系检验和体外实验来了解它们在影响 基因表达作为表达数量性状位点，影响细胞内外APP/Aβ 和tau蛋白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的 AD相关基因和通路，并揭示潜在的可能机制。

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.