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

确定阿尔茨海默病和相关痴呆症神经病理学的遗传病因

• 批准号: 10612832
• 负责人: Gary Wayne Beecham
• 金额: $ 74.13万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612832
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Australia; Autopsy; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular Trauma; Clinic; Clinical; Communities; Complex; Complex Mixtures; Data; Data Analyses; Data Set; Dementia; Diagnostic; Disease; Elderly; Europe; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Variation; Genetic study; Genomic approach; Genomics; Genotype; Goals; Heritability; Impaired cognition; Individual; Injury; Japan; Knowledge; Lesion; Lewy Body Disease; Molecular; Neurofibrillary Tangles; Pathologic; Persons; Phenotype; Population; Sample Size; Sampling; Senile Plaques; Techniques; Testing; Variant; clinical diagnosis; comorbidity; density; genetic variant; genome sequencing; genome-wide; hippocampal sclerosis; neuropathology; next generation sequence data; novel; protein distribution; response to injury; tool; trait; variant of interest; whole genome

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.

项目摘要 在美国、欧洲、日本和澳大利亚进行的多项基于人口和社区的研究， 在临床诊断为 阿尔茨海默病（AD）痴呆。虽然通常包括神经炎性斑块（NP）和神经炎性斑块， 在神经纤维缠结（NFT）中，这些标志性病变的区域水平和分布程度是可变的。此外，本发明还 超过一半的AD痴呆患者在大脑中存在其他共病病变， 隔离可以诊断痴呆-AD相关痴呆（ADRD）。其中包括大脑淀粉样蛋白 脑血管病（CAA）、血管性脑损伤（VBI）、路易体病（LBD）和海马硬化 老年人（HS），除其他外。事实上，临床诊断为AD痴呆的个体经常表现出 AD病变和共病病变的复杂混合，使得不清楚每种病变在多大程度上促成了 认知能力下降和痴呆我们假设，损伤和反应的机制， 产生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。 除了少数例外，AD的遗传研究将遗传变异与AD的临床诊断相关联。 AD痴呆上述共病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（常见假设）， 存在共病病变，还是两者都有？只有两项研究试图解决这一限制。作为核心 分析阿尔茨海默病遗传学联盟（U 01 AG 032984），我们的研究AD神经病理 变化是这些研究中最大的，大约有4900例脑尸检。然而，即使是最初的 研究受到样本量、平台和不太复杂的分析工具的限制。 为了解决这些局限性，并提高我们对痴呆症全谱的认识， 神经病理学，我们提出了一个基因组学研究的标志性AD病变连同共病病变 与ADRD有关。本研究将扩大神经病理学受试者的样本量，将扩大努力 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 理解特质之间的关系。当成功完成后，我们的结果将指向新的， AD或ADRD的每种病理性病变的相关分子贡献者，无论是单独还是联合 组合.为了实现这些目标，我们提出了四个具体目标。SA 1：识别遗传变异 通过全基因组测序和全基因组基因分型与标志性AD病变相关; SA 2：确定 与老年人大脑中常见的共病病变相关的遗传变异; SA 3： 通过评估性状间的混杂和遗传相关性来确定性状间的遗传景观; 和SA 4：确定区域，细胞和病变中鉴定的选定基因的蛋白质产物的分布。 SA 1 -2

项目成果

AI-enabled in silico immunohistochemical characterization for Alzheimer's disease.

• DOI: 10.1016/j.crmeth.2022.100191
• 发表时间: 2022-04-25
• 期刊: Cell reports methods