Genetic Architecture of Alzheimer’s disease Proteinopathies

项目摘要/摘要 为了加强和集中对阿尔茨海默病(AD)特定蛋白病变的研究，2018年 国家老龄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特征来定义AD，这些特征可以在尸检或 通过生物标志物而不是其非特定的神经退行性和临床综合征特征活着的人。 在NIA-AA活体研究框架提出的三个生物标志物中(淀粉样β蛋白(Aβ)， 病理性tau和神经变性)，只有两种AD特异性蛋白病变(Aβ和病理性tau)是 被认为是阿尔茨海默病生物学定义的义务，而神经退行性变，尽管有助于 认知障碍是完全表现出来的疾病的一部分，也可以发生在其他大脑障碍和 因此不是AD所特有的。在活人中对阿尔茨海默病的这种协调的生物学定义的目的 包括临床前阶段是为了将AD与其他类型的脑部疾病和痴呆症区分开来，以 加速并专注于AD特异性蛋白病变的研究，这些疾病在临床之前几十年就表现出来了 AD首发症状的表现，以加深对AD潜在机制的了解 临床表现，并使用(和发现)针对性的疾病修改干预措施，可以预防或 延缓AD症状的出现。 我们持续和长期的研究兴趣与NIA-AA在生活中的研究框架非常吻合 我们已经对脑脊液Aβ42/tau水平进行了全基因组相关性研究的人群 和β在脑中的沉积，用淀粉样蛋白-正电子发射计算机断层扫描测量，并确定了已知和新的关联 APOE和非APOE区域。然而，识别出的信号不能解释所有的表型变异。 两种AD特有的蛋白病变或内表型。在这里，我们提出了一项合作研究， 该领域的领先专家继续努力描绘两种AD的完整遗传基础- 特异性蛋白质病(Aβ和病理性tau)全基因组测序 和大淀粉样蛋白-正电子发射计算机断层扫描和脑脊液Aβ42/tau数据集，显示痴呆症的临床结果，然后测试 已识别的显著变异对下游神经退行性变标志物的影响，并进行广泛的研究 生物信息学和功能研究。此应用程序的主要目标是执行和分析WGS 在足够强大的大型发现样本中，具有良好特征的Aβ和Tau数据以及临床 痴呆识别与Aβ和tau病理相关的假定功能变异的结果如下 通过用Aβ和Tau数据在独立的大样本中重复(目标1-2)。我们将整合基因 创建多基因风险评分以预测Aβ和tau病理的信息，并将检查 AD病理相关变异与下游神经退行性变、共存的神经病理的作用 阿尔茨海默病与阿尔茨海默病的风险和发病年龄(Aim3)。最后，我们将从功能上描述基因 使用生物信息学、因果检验和体外实验来了解它们在影响 基因表达作为影响细胞内外APP/Aβ的表达数量性状基因座 和tau水平，以及髓系细胞功能。这项研究的成功完成将有助于识别小说 AD相关基因和途径，并揭示AD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.