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: 10372972
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372972
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Australia; Autopsy; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular Trauma; Clinic; Clinical; Communities; Complex; Complex Mixtures; Data; 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; Japan; Knowledge; Lesion; Lewy Body Disease; Molecular; Neurofibrillary Tangles; Pathologic; Persons; Phenotype; Population; Sample Size; Sampling; Senile Plaques; Techniques; Testing; Variant; base; clinical diagnosis; comorbidity; density; genetic variant; genome sequencing; genome-wide; hippocampal sclerosis; interest; neuropathology; next generation sequence data; novel; protein distribution; response to injury; tool; trait; 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个人口和社区研究都 反复观察到具有临床诊断的个体的复杂神经病理学变化 阿尔茨海默氏病（AD）痴呆症。阿尔茨海默氏病（AD）痴呆症。尽管通常包括神经质斑块（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程度是可变的。此外， 超过一半的AD痴呆患者在大脑中有其他合并病变，当 隔离可以是痴呆症的诊断 - 与广告相关的痴呆症（ADRDS）。这些包括脑淀粉样蛋白 血管病（CAA），血管脑损伤（VBI），Lewy身体疾病（LBD）和海马硬化症 老年人（HS）等。实际上，患有AD痴呆的临床诊断的个体经常显示 广告病变和合并病变的复杂混合物，使其不清楚每个人的贡献程度 该人的认知能力下降和痴呆症。我们假设伤害机制和对 产生这些不同疾病特异性脑病变的损伤受到不同遗传因素的影响。 除少数例外，AD的遗传研究具有相关的遗传变异，并具有临床诊断 痴呆症。上述合并症的复杂性是解释这些数据的严重限制。是 与AD痴呆症的关联与AD的标志性病变有关（常见假设），可变 目前的合并病变，还是两者兼而有之？只有两项研究试图解决这一限制。作为核心 阿尔茨海默氏病遗传学联盟（U01AG032984）的分析，我们对AD神经病理学的研究 这些研究中有大约4900个脑尸检的变化。但是，即使是这个最初的 研究受样本量，平台和较不复杂的分析工具的限制。 解决这些局限性并提高我们对痴呆症的全部知识 神经病理学，我们提出了一项关于标志性广告病变的基因组学研究以及合并症 与ADRD相关联。这项研究将扩大神经病理学主题的样本量，将扩大努力 包括下一代序列数据，并将实施更高级的统计技术以更好 了解特征之间的关系。成功完成后，我们的结果将指向新颖， 单独或在 组合。为了实现这些目标，我们提出了四个具体目标。 SA1：确定遗传变异 通过整个基因组测序和全基因组基因分型与Hallmark AD病变有关； SA2：识别 老年人大脑中通常存在与合并症相关的遗传变异； SA3： 通过评估性状的混杂和遗传相关性来确定特征遗传景观； 和，SA4：确定鉴定出在 SA1-2。