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: 10261443
• 负责人: JAMES Robert CONNOR
• 金额: $ 19.97万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261443
• 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.

项目总结 阿尔茨海默病(AD)表现不均匀，表现为局部脑结构 对病理和疾病进展的不同易感性导致疾病病程暂时性 变种。我们先前由美国国立卫生研究院赞助的工作表明，HFEH63D单核苷酸 多态(SNP)异质性地改变大脑的完整性。这种错义突变是最常见的 广泛存在于人类基因组中；世界上近16%的人口是携带者。HFE基因 错综复杂地参与全身铁稳态，并被假设参与AD；然而， 不一致的发现还没有确定HFE SNPs的方向性或与AD病因的关系。 我们最近令人兴奋的初步数据揭示了HFEH63D-AD携带者之间的负相关 和疾病状态的生物标志物，特别是表明晚期髓鞘形成明显减少 脑白质完整性和对疾病病理的易感性增加。不知道为什么这么晚- 在AD的早期发病过程中，髓鞘白质完整性降低。HFEH63D基因 提供了一个独特的机会来理解AD的病理和疾病过程的机制 在区域上加剧，以及告知可能改变疾病进展的程序。 找到调节AD的因素非常重要，特别是像这样常见的因素 HFE基因多态性。与阿尔茨海默病有关的遗传因素在很大程度上是基于家族性的 起病早，病理性诱发。散发性AD似乎既有环境因素也有遗传因素 协同作用最终导致疾病的因素。数据表明，不同的趋同 阿尔茨海默病的临床表现，形成起病年龄和时间域的疾病谱 进步的力量。在理解大脑是如何在AD过程中和在 正常衰老，我们的工作旨在专门解决这一知识鸿沟。 这项研究将影响未来对AD和AD患者动态脑和认知变化的研究 与年龄相关的大脑自然衰老。H63D基因型提供了一个独特的机会来询问 地区性AD病理与病程的关系及对未来的启示 可能改变疾病进展的程序。这一提议的中心假设是，HFE 基因分型降低了大脑的完整性，增加了病理性，加速了阿尔茨海默氏症的发展。 我们建议：1)描述晚期髓鞘白质完整性的纵向进展 在HFEH63D阿尔茨海默病携带者中，2)确定认知状态和大脑的轨迹 轻度认知障碍和年龄匹配对照的完整性以确定HFEH63D SNP是否改变 认知障碍的发病，以及3)表征淀粉样β蛋白沉积的纵向进展和 HFEH63D阿尔茨海默氏症、MCI和年龄匹配的对照组的脑代谢。