Cell-specific genomic features of Alzheimer's disease progression

年龄是阿尔茨海默病（AD）的主要危险因素。人类研究关注的是 转录组学和衰老表观基因组学之间的联系及其与AD的关系为我们提供了很大的希望， 揭示AD的分子基础并提供新的治疗靶点。转录组和表观基因组 迄今为止的研究报告受到了一些方法学问题的阻碍，特别是使用 异质细胞混合物。使用来自1，263名参与者的纯化单核细胞的转录组学谱， 多种族动脉粥样硬化研究（梅萨），我们报告了一个共表达的氧化应激的转录网络， 磷酸化（OXPHOS）基因随着年龄的增长而下降。我们下面的转录组学分析表明， 这21个基因的OXPHOS网络（FDR <0.05）与认知功能正相关。这些 人类数据，结合我们与单核细胞线粒体功能相关的非人灵长类动物数据， 额叶皮质组织和转基因小鼠的最新数据显示线粒体功能障碍在 提示单核细胞转录谱可能反映了大脑生物能量功能障碍， AD.鉴于在小鼠中出现的证据表明，单核细胞可以渗入大脑并接管免疫系统， 通过监测，我们的数据还表明单核细胞功能的改变可能影响AD。不过，我们的十字架- 部分人类数据不能确定OXPHOS的基因组改变是否是以下疾病的原因或结果： AD.这项研究的目的是确定细胞特异性基因网络的影响，特别是衰老- 相关的网络，如OXPHOS，通过基因组的综合分析， 表观基因组学和转录组学数据在一个纵向的社区为基础的研究。梅萨的深度表型 队列，具有在考试5（2010-11）收集的独特的现有表观基因组学，转录组学和认知数据， 提供了理想的研究人群。我们建议重复表观基因组，转录组和认知 在考试6（2016-17）的评估，并执行统一数据集的认知电池，使 轻度认知障碍（MCI）和阿尔茨海默氏痴呆症的确定在考试6和三年后， 梅萨队列的一个子集（N= 1，200），以实现以下特定目标：1）确定是否老化- 转录组/表观基因组谱的相关变化预测6年随访期间的认知能力下降; 2） 确定转录组/表观基因组谱中的衰老相关变化是否可预测AD的发生 三年随访;和3）为了确定线粒体活性和含量是否存在差异， 其可从OXPHOS改变预测，与AD的发展有关。这个大的，有前景的 多组学研究将采取一种新的方法，关注人类衰老相关基因网络 同源细胞，以确定新的生物标志物的AD发展，一个关键的一步，了解 细胞特异性机制，并为早期干预提供线索。

Age is the primary risk factor for Alzheimer's disease (AD). Human studies that focus on the connections between transcriptomics and epigenomics of aging and their relationship to AD hold great promise for unraveling the molecular basis of AD and providing novel therapeutic targets. Transcriptomic and epigenomic studies reported to date have been hampered by a number of methodologic issues, especially the use of heterogeneous cell mixtures. Using transcriptomic profiles in purified monocytes from 1,263 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we reported a transcriptional network of co-expressed oxidative phosphorylation (OXPHOS) genes that decline with age. Our following transcriptomic analysis demonstrated that this OXPHOS network of 21 genes (FDRs<0.05) were positively associated with cognitive function. These human data, combined with our non-human primate data correlating mitochondrial function of monocytes and frontal cortex tissue and recent data in transgenic mice showing a causal role of mitochondrial dysfunction in AD, suggest that monocyte transcriptional profiles may reflect brain bioenergetic dysfunctions linking age to AD. Given emerging evidence in mice that monocytes can infiltrate the brain and take over immune surveillance, our data also suggest that altered monocyte function may affect AD. Nevertheless, our cross- sectional human data cannot determine whether genomic alteration of OXPHOS is a cause or consequence of AD. The goal of the proposed study is to determine the impact of cell specific gene networks, especially aging- related networks such as OXPHOS, on the development of AD through an integrated analysis of genomic, epigenomic and transcriptomic data in a longitudinal community-based study. The deeply phenotyped MESA cohort, with unique existing epigenomic, transcriptomic and cognitive data collected at Exam 5 (2010-11), offers an ideal study population. We propose to repeat the epigenomic, transcriptomic and cognitive assessment at Exam 6 (2016-17) and perform the cognitive battery of the Uniform Data Set to enable ascertainment of mild cognitive impairment (MCI) and Alzheimer's dementia at Exam 6 and three years later in a subset of MESA cohort (N=1,200) to achieve the following specific aims: 1) To determine whether aging- related changes in transcriptomic/epigenomic profiles predict cognitive decline over a 6-year follow-up; 2) To determine whether aging-related changes in transcriptomic/epigenomic profiles predict development of AD over a three-year follow-up; and 3) To determine whether differences in mitochondrial activity and content, which would be predicted from the OXPHOS alterations, relate to development of AD. This large, prospective multi-omic study will take a novel approach of focusing on aging-related gene networks in human homogeneous cells to identify new biomarkers for AD development, a crucial step forward in understanding cell-specific mechanisms and providing clues to early intervention.