HFE SNP Effect on Alzheimer's Regional Brain Susceptibility

HFE SNP 对阿尔茨海默病区域脑易感性的影响

• 批准号: 9979229
• 负责人: JAMES Robert CONNOR
• 金额: $ 24.03万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979229
• 关键词: Acceleration; Address; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Area; Attenuated; Biological Markers; Brain; Clinical; Cognitive; Data; Data Set; Diffusion; Disease; Disease Progression; Etiology; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; HFE gene; Homeostasis; Human Genome; Impaired cognition; Incidence; Inflammatory; Iron; Knowledge; Light; Magnetic Resonance Imaging; Missense Mutation; Modeling; Mutation; Nerve Degeneration; Neurons; Onset of illness; Pathogenesis; Pathologic; Pathology; Population; Positron-Emission Tomography; Predisposition; Procedures; Process; Production; Proteins; Research; Single Nucleotide Polymorphism; Stratification; Structure; Time; United States National Institutes of Health; Variant; Work; abeta deposition; age related; base; brain metabolism; brain tissue; cognitive change; cohort; design; early onset; fluorodeoxyglucose positron emission tomography; gray matter; longitudinal analysis; mild cognitive impairment; normal aging; prodromal Alzheimer' s disease; serial imaging; white matter

PROJECT SUMMARY Alzheimer’s disease (AD) presents heterogeneously with regional brain structures demonstrating distinct susceptibility to pathology and disease progression resulting in disease course temporal variation. Our prior NIH sponsored work demonstrated that the HFEH63D single nucleotide polymorphism (SNP) heterogeneously alters brain integrity. This missense mutation is one of the most widespread in the human genome; with nearly 16% of the world’s population as carriers. The HFE gene is intricately involved in systemic iron homeostasis and is hypothesized to be involved in AD; however, inconsistent findings have not determined directionality or the relationship of HFE SNPs to AD etiology. Our exciting recent preliminary data brings to light a negative relationship between HFEH63D-AD carriers and biomarkers of disease status, specifically demonstrating an apparent decrease in late-myelinating white matter integrity and increased susceptibility to disease pathology. It is unknown why late- myelinating white matter integrity is reduced during early AD pathogenesis. The HFEH63D genotype presents a unique opportunity to understand the mechanism wherein AD pathology and disease course are regionally exacerbated, as well as inform procedures that may alter disease progression. Finding factors that modulate AD is highly significant, particularly ones that are as common as this HFE polymorphism. Genetic factors involved in AD have largely been established based on familial early onset and pathology induction. Sporadic AD appears to have both environmental and genetic factors that synergistically culminate into disease. Data suggest a heterogeneous convergence towards the clinical manifestation of AD, forming a disease spectrum along domains of age of onset and time of progression. There exists a gap in understanding how the brain is modified during AD course and in normal aging, our work aims to specifically address this knowledge gap. This research will impact future work on dynamic brain and cognitive changes altered in AD and natural age-related brain senesce. The H63D genotype presents a unique opportunity to interrogate the relationship between regional AD pathology and disease course, as well as inform future procedures that may alter disease progression. The central hypothesis for this proposal is that the HFE genotype reduces brain integrity, increases pathology, and accelerates Alzheimer’s trajectory. We propose to: 1) characterize the longitudinal progression of late-myelinating white matter integrity in HFEH63D Alzheimer’s disease carriers, 2) determine the trajectory of cognitive status and brain integrity in mild-cognitive impairment and age-matched controls to establish if the HFEH63D SNP alters onset of cognitive loss, and 3) characterize the longitudinal progression of amyloid-beta deposition and brain metabolism in HFEH63D Alzheimer’s, MCI, and age-matched controls.

项目摘要 阿尔茨海默氏病（AD）与区域大脑结构异质表明 对病理和疾病进展的明显敏感性导致疾病病程临时 变化。我们先前的NIH赞助工作证明了HFEH63D单核苷酸 多态性（SNP）异质地改变了大脑完整性。这个错义突变是最多的突变之一 人类基因组中的宽度；世界上近16％的人口是载体。 HFE基因 与全身铁稳态相关，并被认为参与了AD；然而， 不一致的发现尚未确定方向性或HFE SNP与AD病因的关系。 我们最近令人兴奋的初步数据使HFEH63D-AD运营商之间的负相关关系 和疾病状况的生物标志物，特别表明晚期明显下降 白质完整性并增加了对疾病病理学的敏感性。不知道为什么 在早期AD发病机理期间，白质完整性降低。 HFEH63D基因型 提出了一个独特的机会来了解AD病理学和疾病病程的机制 区域性加剧，并为可能改变疾病进展的程序提供信息。 查找调节广告的因素非常重要，尤其是与此一样普遍的因素 HFE多态性。广告中涉及的遗传因素已基于家族建立 早期发作和病理诱导。零星的广告似乎具有环境和遗传 协同最终导致疾病的因素。数据表明与 AD的临床表现，沿着年龄和时间的域形成疾病谱 进展。在了解广告课程和中间如何修改大脑的情况下存在差距 正常的老化，我们的工作旨在特别解决这一知识差距。 这项研究将影响未来在动态大脑上的工作，并且AD和认知变化发生了变化 自然与年龄有关的脑传感器。 H63D基因型提供了询问的独特机会 区域广告病理学与疾病课程之间的关系，并为未来提供信息 可能改变疾病进展的程序。该提议的中心假设是HFE 基因型可降低大脑完整性，增加病理，并加速阿尔茨海默氏症的轨迹。 我们建议：1）表征晚白质完整性的纵向进展 在HFEH63D阿尔茨海默氏病载体中，2）确定认知状况和大脑的轨迹 轻度认知障碍和年龄匹配的控件的完整性，以确定HFEH63D SNP是否改变 认知丧失的发作，以及3）表征淀粉样蛋白β沉积和 HFEH63D阿尔茨海默氏症，MCI和年龄匹配的对照中的脑代谢。