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

这项研究的长期目标是研究DNA甲基化模式和存在之间的联系。 墨西哥裔美国人（MA）和非西班牙裔白人中阿尔茨海默病（AD）的进展 （NHW）。在这里，我们将讨论PAR-19-070（阿尔茨海默病当前主题研究）的目标 及其相关痴呆）- NOT-AG-18-047 -通过利用正在进行的HABLE队列（R 01 AG 054073）， 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的年龄，性别， 和诊断匹配的参与者利用HABLE生物储存库（MCI n=45，对照n=45）。我们 在正常衰老对照组中， 被诊断为MCI的人。功能基因集分析确定四个基因集为显着的。基因 本体论和途径分析强调了神经元细胞死亡、代谢功能障碍和炎性 流程.利用贝叶斯基因集富集，我们发现MCI诊断与过程相关， 集中在高血压、糖尿病、听力和嗅觉丧失、突触转运蛋白活性和 炎症这些结果将外周代谢失调和炎症与认知能力下降联系起来， 表明MA认知能力下降是代谢应激相关因素的表现。 通过利用HABLE生物储存库，我们将进行纵向表观基因组关联研究 （EWAS）对来自n=1800名HABLE（n=900 MA; n=900 NHW）参与者的生物储存库数据进行分析，以确定 在循环白细胞中的差异甲基化DNA，以解决两个特定目的： 目标1.识别与白细胞中DNA甲基化相关的DNA甲基化模式， 墨西哥裔美国人和非西班牙裔白人中阿尔茨海默病的进展。 目标二。确定与糖尿病的患病率和进展相关的白细胞DNA甲基化模式 AT（N）定义了墨西哥裔美国人和非西班牙裔白人中AD的生物标志物。 目标1的结果将通过与资助项目（1 R 01 AG 061022 -01）的数据进行比较来验证， 评估白细胞meDNA在SOL-INCA队列中AD病因学中的作用。目标2 meDNA结果 与淀粉样蛋白负荷相关的模式将与新IDEAS研究的数据进行比较。 本次提案具有高度的重大意义和创新性：1）提案工作是首次大规模 与AT（N）框架定义的病理标志物相关的meDNA模式的纵向检查 MA中的AD; 2）本研究直接符合IIA定义的AD/ADRD研究的里程碑， 3）这项研究的数据将与HABLE数据库合并，并向公众提供， 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).