HFE SNP Effect on Alzheimer's Regional Brain Susceptibility

项目摘要 阿尔茨海默病（AD）表现出不均匀的局部脑结构， 对病理学和疾病进展的不同易感性导致疾病病程短暂 变化量我们先前NIH赞助的工作表明，HFEH 63 D单核苷酸 多态性（SNP）不均匀地改变大脑的完整性。这种错义突变是 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 复杂地参与全身铁稳态，并被假设与AD有关;然而， 不一致的发现没有确定HFE SNP与AD病因学的方向性或关系。 我们最近令人兴奋的初步数据揭示了HFEH 63 D-AD携带者之间的负相关关系 和疾病状态的生物标志物，特别是证明了髓鞘形成晚期的明显减少， 白色物质的完整性和对疾病病理学的易感性增加。不知道为什么迟到了- 髓鞘形成白色物质的完整性在早期AD发病过程中降低。HFEH 63 D基因型 提供了一个独特的机会，了解机制，其中AD病理和疾病过程 区域性恶化，以及通知可能改变疾病进展的程序。 找到调节AD的因素是非常重要的，特别是像这样常见的因素。 HFE多态性。涉及AD的遗传因素在很大程度上是基于家族遗传学建立的。 早期发病和病理诱导。散发性AD似乎既有环境因素， 协同作用最终导致疾病的因素。数据显示， AD的临床表现，沿发病年龄和时间沿着域形成疾病谱 的进步。在理解AD过程中大脑是如何改变的方面存在着差距， 正常老化，我们的工作旨在专门解决这一知识差距。 这项研究将影响未来的工作动态大脑和认知变化改变AD和 与年龄有关的自然大脑衰老H63 D基因型提供了一个独特的机会， 区域性AD病理学和疾病进程之间关系，以及未来的信息 可能改变疾病进展的程序。该提议的核心假设是， 基因型降低了大脑的完整性，增加了病理学，加速了阿尔茨海默氏症的发展。 我们建议：1）表征晚髓鞘形成白色物质完整性的纵向进展 在HFEH 63 D阿尔茨海默病携带者中，2）确定认知状态和大脑的轨迹 在轻度认知障碍和年龄匹配的对照组中，确定HFEH 63 D SNP是否改变了 认知丧失的发作，和3）表征淀粉样蛋白-β沉积的纵向进展， HFEH 63 D阿尔茨海默氏症、MCI和年龄匹配对照的脑代谢。

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.