New computational tools for understanding and predicting AD via age-associated DNA methylation changes

阿尔茨海默病(AD)是最常见的神经退行性疾病，晚发性AD影响约1 在美国，65岁以上的人中有9人。美国日益增长的老年人口使老年痴呆症成为主要公众 健康问题，也是经济成本最高的疾病之一。目前，一个主要的挑战是缺乏可靠的、 微创、廉价的生物标记物有助于诊断、预后和最终开发新的 AD治疗策略。AD生物标志物的一个潜在来源是DNA甲基化(DNaM)。中的更改 DNaM与衰老和阿尔茨海默病有关。此外，dNaM相对稳定，可以容易地 检测到。DNaM是基因组和环境界面上的一种表观遗传机制，它受到影响 由于衰老和许多生活方式因素，如吸烟、饮食和锻炼，这反过来可能会改变患心脏病的风险 广告。在过去的几年里，我们已经为dNaM和其他软件开发了几个创新的开源软件 基因组学数据分析。在本提案中，根据我们以前开发和应用工具的经验 对于大规模异质数据集的综合基因组分析，我们建议协调一个大的 用于阐明dNaM在衰老和AD中的作用的dNaM数据集的数量，以开发 传播分析结果，并开发为预测AD表型量身定做的表观遗传学时钟。我们 假设一些基于dNaM的监管变化与衰老和AD都相关，并且某些年龄- 相关的dNaM改变也有助于AD的发生和进展。在目标1中，我们将集合、协调 并对在脑和血液样本中测量的大量dNaM老化数据集进行Meta分析，以确定 与衰老和AD相关的dNaM变化，并确定与年龄相关的dNaM差异，这些差异也 对AD做出贡献。我们将开发两个工具：(1)可搜索的Web界面，用于阐明DNA的作用 衰老和阿尔茨海默病中的甲基化以及(2)用于执行dNaM荟萃分析的开源R包 甲基化区域。在目标2中，我们将开发一种新的表观遗传学时钟，用于预测AD表型。这个 新的表观遗传时钟的诊断和预后价值将使用可用的脑脊液生物标记物进行评估 和临床认知结果，并与已知的临床和遗传因素进行比较，以及目前 可用的血浆生物标志物。可搜索的Web界面将显著提高我们的理解和 能够对AD中与年龄相关的表观遗传学变化的作用有新的生物学见解。新的表观遗传时钟 为预测AD表型而量身定做的将促进替代生物标志物的开发，这些生物标志物提供了 在临床试验中监测疾病进展以及评估个体化风险概况的客观性 用于AD的诊断和预后。该项目的成功完成也将为我们提供计算能力 可轻松调整和应用的管道和工具，用于分析为其他类型的 痴呆症。

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with late-onset AD affecting about 1 in 9 people over 65 years old in the US. The increasing elderly population in the US makes AD a major public health concern and one of the most financially costly diseases. Currently, a major challenge is the lack of reliable, minimally invasive, inexpensive biomarkers to aid the diagnosis, prognosis, and ultimately development of new AD treatment strategies. One potential source of biomarkers for AD is DNA methylation (DNAm). Changes in DNAm have been implicated in both aging and AD. Moreover, DNAm is relatively stable and can be easily detected. DNAm is an epigenetic mechanism at the interface of the genome and environment, and it is influenced by aging and many lifestyle factors such as smoking, diet, and exercise, which in turn might modify the risk of AD. In the past few years, we have developed several innovative open-source software for DNAm and other genomics data analyses. In this proposal, building on our previous experiences in developing and applying tools for integrative genomics analyses of large-scale heterogeneous datasets, we propose to harmonize a large number of DNAm datasets to clarify the role of DNAm in aging and AD, to develop a web interface that disseminates the analyses results, and to develop epigenetic clocks tailored for predicting AD phenotypes. We hypothesize a number of DNAm-based regulatory changes are relevant to both aging and AD, and some age- associated DNAm changes also contribute to AD onset and progression. In Aim 1, we will aggregate, harmonize, and meta-analyze a large number of DNAm aging datasets measured in brain and blood samples to identify DNAm changes associated with aging and AD, and determine age-associated DNAm differences that also contribute to AD. We will develop two tools: (1) a searchable web interface that clarifies the role of DNA methylation in aging and AD and (2) an open-source R package for performing meta-analyses of DNAm methylation regions. In Aim 2, we will develop a new epigenetic clock tailored for predicting AD phenotypes. The diagnostic and prognostic values of the new epigenetic clock will be evaluated using available CSF biomarkers and clinical cognitive outcomes and compared with known clinical and genetic factors, as well as currently available plasma biomarkers. The searchable web interface will significantly enhance our understanding and enable new biological insights on the role of age-associated epigenetic changes in AD. The new epigenetic clock tailored to predicting AD phenotypes will facilitate the development of surrogate biomarkers that provide a degree of objectivity for monitoring disease progression in clinical trials, as well as assessing individualized risk profiles for AD diagnosis and prognosis. The successful completion of the project will also provide us with computational pipelines and tools that can be easily adapted and applied to analyze datasets generated for other types of dementias.