Epigenetic Risk Factors for AD Age at Onset and Health Disparities: HABLE Epigenetics Study

这项研究的长期目标是检查DNA甲基化模式和存在之间的联系 和阿尔茨海默病(AD)在墨西哥裔美国人(MA)和非西班牙裔白人中的进展 (Nhw)。在这里，我们将阐述PAR-19-070(阿尔茨海默病当前主题研究)的目标 及其相关的痴呆症)-不是-AG-18-047-通过利用正在进行的Hable队列(R01AG054073)来 确定与MA和NHW中AD的存在和进展相关的表观遗传因素。 在我们之前的工作和最近的hable数据中，我们检查了n=90个年龄、性别之间的dna甲基化模式。 和利用Hable生物资料库的诊断匹配的参与者(MCI n=45，对照n=45)。我们 确定了10个CpG位点和4个区域在正常衰老对照中存在差异甲基化 被诊断为MCI的个人。功能基因集分析确定了四个显著的基因集。基因 本体和通路分析强调神经细胞死亡、代谢功能障碍和炎症 流程。利用贝叶斯基因集浓缩，我们发现MCI诊断与过程有关 集中于高血压、糖尿病、听力和嗅觉丧失、突触转运体活性和 发炎。这些结果将外周代谢紊乱和炎症与认知能力下降和 提示多发性硬化患者的认知功能下降是代谢应激相关因素的表现。 通过利用Hable生物库，我们将进行一项纵向的表观基因组范围的关联研究 (Ewas)来自n=1800 Hable(n=900 MA；n=900 nhw)参与者的生物信息库数据，以识别 循环白细胞中差异甲基化DNA以解决两个特定目的： 目的1.确定白细胞中DNA甲基化模式与存在和 阿尔茨海默病在墨西哥裔美国人和非西班牙裔白人中的进展。 目的2.确定白细胞中的DNA甲基化模式与糖尿病的流行和进展有关 在墨西哥裔美国人和非西班牙裔白人中，AT(N)定义了AD的生物标志物。 目标1的结果将通过与一个资助项目(1R01AG061022-01)的数据进行比较来验证，该项目是 在Sol-Inca队列中评估白细胞meDNA在AD病因中的作用。目标2：meDNA检测结果 与淀粉样蛋白负荷相关的模式将与新想法研究的数据进行比较。 目前的提案具有很高的意义和创新性：1)拟议的工作是第一个大规模的 与AT(N)框架定义的病理标记物相关的meDNA图谱的纵向检查 MA中的AD；2)本研究直接满足NIA定义的AD/ADRD研究中的里程碑 人口；3)这项研究的数据将与HABLE数据库合并，并向 科学界和阿尔茨海默病测序项目(ADSP)和ADSP-Functional 基因组学联盟(ADSP-FGC)。

The long-term goal of this research is to examine the link between DNA methylation patterns and presence and progression of Alzheimer’s disease (AD) among Mexican Americans (MA) and non-Hispanic whites (NHW). Here we will address the aims of PAR-19-070 (Research on Current Topics in Alzheimer's Disease and Its Related Dementias) – NOT-AG-18-047 – by leveraging the ongoing HABLE cohort (R01AG054073) to identify the epigenetic factors associated with presence and progression of AD among MAs and NHWs. In our prior work and recent HABLE data, we examined DNA methylation patterns among n= 90 age, gender and diagnosis-matched participants leveraging the HABLE Biorepository (MCI n=45, controls n=45). We identified 10 CpG sites and four regions to be differentially methylated in normally aging controls relative to individuals diagnosed with MCI. Functional gene-set analysis identified four gene sets as significant. Gene ontology and pathway analysis highlighted neuronal cell death, metabolic dysfunction and inflammatory processes. Using Bayes gene set enrichment, we found MCI diagnosis was associated with processes converging on hypertension, diabetes, loss of hearing and olfaction, synaptic transporter activity and inflammation. These results link peripheral metabolic dysregulation and inflammation with cognitive decline and suggest that cognitive decline in MAs is a manifestation of factors related to metabolic stress. By leveraging the HABLE Biorepository, we will conduct a longitudinal Epigenome-Wide Association Study (EWAS) on biorepository data from n=1800 HABLE (n=900 MA; n=900 NHW) participants to identify differentially methylated DNA in circulating leukocytes to address two Specific Aims: Aim 1. Identify DNA methylation patterns in leukocytes that are associated with presence and progression of Alzheimer’s disease among Mexican Americans and non-Hispanic whites. Aim 2. Identify DNA methylation patterns in leukocytes that covary with prevalence and progression of AT(N) defined biomarkers of AD among Mexican Americans and non-Hispanic whites. Aim 1 results will be validated by comparison with data from a funded project (1R01AG061022-01) that is assessing the role of leukocyte meDNA in AD etiology in the SOL-INCA cohort. Aim 2 results for meDNA patterns associated with amyloid burden will be compared to data from the New IDEAS study. The current proposal is highly significant and innovative: 1) The proposed work is the first large-scale longitudinal examination of meDNA patterns associated with AT(N) Framework-defined pathological markers of AD among MAs; 2) this study directly meets NIA-defined milestones for AD/ADRD research among diverse populations; 3) data from this study will be merged with the HABLE database and made publicly available to the scientific community and the Alzheimer’s Disease Sequencing project (ADSP) and ADSP-Functional Genomics Consortium (ADSP-FGC).