Identifying the Genetic Etiology of Neuropathology for Alzheimer Disease and Related Dementias

项目总结 在美国、欧洲、日本和澳大利亚进行了多项基于人口和社区的研究 曾多次观察到临床诊断为 阿尔茨海默病(AD)痴呆。尽管通常包括神经炎性斑块(NP)和神经原纤维 缠结(NFT)，这些标志性病变的区域水平和分布范围是不同的。另外， 超过一半的阿尔茨海默病患者有其他脑部共病病变，当出现在 隔离可以诊断痴呆症--AD相关痴呆症(ADRD)。这些包括大脑淀粉样蛋白 血管病(CAA)、血管性脑损伤(VBI)、路易体病(LBD)和海马硬化 老年人(HS)等。事实上，临床诊断为阿尔茨海默病的人经常表现出 AD病变和共病病变的复杂组合，使人们不清楚各自导致的程度 认知功能减退和痴呆症。我们假设，损伤和反应的机制 造成这些不同疾病特异性脑损伤的损伤受到不同遗传因素的影响。 除了极少数例外，阿尔茨海默病的遗传学研究已经将遗传变异与临床诊断联系起来。 老年痴呆症。上述并存的复杂性严重限制了对这些数据的解释。是 与AD标志性病变相关的AD痴呆的相关性(共同假设)，变量 出现共患皮损，还是两者兼而有之？只有两项研究试图解决这一局限性。作为核心 阿尔茨海默病遗传学联合体(U01AG032984)分析--我们的阿尔茨海默病神经病理学研究 在这些研究中，变化是规模较大的，大约有4900例脑部尸检。然而，即使是这个最初的 研究受到样本大小、平台和不太复杂的分析工具的限制。 为了解决这些限制，并促进我们对痴呆症全谱系的了解 神经病理学，我们建议对阿尔茨海默病的标志性病变和共病病变进行基因组学研究。 与ADRD相关。这项研究将扩大神经病理学学科的样本量，将努力扩大 包括下一代序列数据，并将实施更先进的统计技术，以更好地 理解特征之间的关系。当成功完成后，我们的结果将指向新奇， AD或ADRD的每一种病理损害的相关分子贡献者，无论是单独的还是 组合。为了实现这些目标，我们提出了四个具体目标。SA1：识别基因变异 通过全基因组测序和全基因组基因分型与标志性AD损害相关；SA2：鉴定 与老年人大脑中常见的共病损害相关的遗传变异；SA3： 通过评估性状间的混淆和遗传相关性来确定性状间的遗传格局； 和SA4：确定选定基因蛋白产物的区域、细胞和病变分布 SA1-2。

PROJECT SUMMARY Multiple population and community based studies conducted across the US, Europe, Japan, and Australia all have repeatedly observed complex neuropathologic changes in individuals with a clinical diagnosis of Alzheimer's disease (AD) dementia. Although usually including neuritic plaques (NP) and neurofibrillary tangles (NFT), the regional levels and extent of distribution of these hallmark lesions are variable. Additionally, more than half of individuals with AD dementia have other comorbid lesions in brain that when present in isolation can be diagnostic of dementia—the AD-Related Dementias (ADRDs). These include cerebral amyloid angiopathy (CAA), vascular brain injury (VBI), Lewy body disease (LBD), and hippocampal sclerosis of the elderly (HS), among others. Indeed, individuals with a clinical diagnosis of AD dementia frequently show a complex mix of AD lesions and comorbid lesions, making it unclear the extent to which each contributed to cognitive decline and dementia in that person. We hypothesize that the mechanisms of injury and response to injury that produce these different disease-specific brain lesions are influenced by differing genetic factors. With few exceptions, genetic studies for AD have associated genetic variants with a clinical diagnosis of AD dementia. The comorbid complexity described above is a serious limitation to interpreting these data. Are the associations with AD dementia related to the hallmark lesions of AD (common assumption), the variably present comorbid lesions, or both? Only two studies have attempted to address this limitation. As a core analysis of the Alzheimer Disease Genetics Consortium (U01AG032984), our study of AD neuropathologic changes was the larger of these studies with approximately 4900 brain autopsies. However, even this initial study was limited by sample size, platform, and less sophisticated analysis tools. To address these limitations and to advance our knowledge of the full spectrum of dementia neuropathology, we propose a genomics study of hallmark AD lesions together with comorbid lesions associated with ADRDs. This study will expand the sample size of neuropathology subjects, will expand efforts to include next-generation sequence data, and will implement more advanced statistical techniques to better understand the relationships between traits. When successfully completed, our results will point to novel, relevant molecular contributors for each of the pathologic lesions of AD or ADRDs, either alone or in combination. To accomplish these goals we propose four Specific Aims. SA1: Identify genetic variants associated with hallmark AD lesions by whole genome sequencing and genome-wide genotyping; SA2: Identify genetic variants associated with comorbid lesions commonly present in brains of older individuals; SA3: Determine the inter-trait genetic landscape by assessing confounding and genetic correlations across traits; and, SA4: Determine regional, cellular, and lesion distribution of protein products of selected genes identified in SA1-2.