Blood DNA Methylation Biomarkers of Alzheimer's Disease

阿尔茨海默病的血液 DNA 甲基化生物标志物

基本信息

批准号：
10055220
负责人：
Reid Spencer Alisch
金额：
$ 59.27万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10055220
关键词：
Address Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease risk Alzheimer’s disease biomarker Auditory Biological Markers Blood Brain Cerebrospinal Fluid Clinical Cognitive Cognitive aging Cost of Illness DNA DNA Methylation Data Dementia Diagnosis Disease Marker Early Intervention Elderly Enrollment Epigenetic Process Etiology Female Foundations Genes Hematological Disease Heritability Human Genome Intervention Investigation Late Onset Alzheimer Disease Location Longevity Mission Neurodegenerative Disorders Neurofilament Proteins Oxidoreductase Participant Pathogenesis Pathway interactions Patients Peripheral Phenotype Population Positioning Attribute Prostaglandins Psychometrics Public Health Reporting Research Risk Risk Factors Sampling Studies Signs and Symptoms Site Specialist Superior temporal gyrus Symptoms Testing Time Tissues Validation Verbal Learning Wisconsin Woman base brain tissue clinical Diagnosis clinical predictors cohort disorder risk epigenome epigenome-wide association studies follow-up genome sequencing human data improved male men methylation biomarker mild cognitive impairment modifiable risk neurogranin neuroimaging novel novel diagnostics outcome forecast phenotypic biomarker phenotypic data primary care setting prognostic tau Proteins tau-1 therapeutic target whole genome

项目摘要

Project Summary Recent array-based epigenome-wide association studies (EWAS) of brain tissue report differential DNA methylation in known and newly recognized late-onset sporadic Alzheimer’s disease (LOAD) genes, thereby underscoring the utility of EWAS in disclosing novel genes and pathways associated with LOAD pathogenesis. As an alternative to the study of samples from donor brains, investigation of DNA methylation in accessible peripheral tissues offers the opportunity to improve LOAD diagnosis and prognosis. Recently, we’ve identified differentially methylated positions (DMPs) in blood that distinguish men and women with and without LOAD at 477 of 769,190 loci in a plurality of genes. Of these DMPs, 17 are shared between DMPs observed using clinical LOAD markers analyzed independently as continuous variables comprising Rey Auditory Verbal Learning Test scores, cerebrospinal fluid total tau (t-tau) and phosphorylated tau 181 (p-tau181) levels, and t-tau/Aβ1–42 (Aβ42), p-tau181/Aβ42, and Aβ42/Aβ1–40 (Aβ40) ratios. In patients with LOAD, 12 of the shared 17 DMPs are hypo- methylated in B3GALT4 (Beta-1,3-galatcosyltransferase 4), a gene previously associated with LOAD in superior temporal gyrus brain tissue, and 5 are hypo-methylated in ZADH2 (Prostaglandin reductase 3), a novel LOAD- associated gene. Together these data reinforce use of blood to identify DMPs associated with dementia that arises from LOAD, leading to the hypothesis that DNA methylation levels in blood may be used to identify novel diagnostic, prognostic, and modifiable therapeutic targets of LOAD. Using a whole-genome-based approach, this proposal builds upon the Wisconsin Alzheimer’s Disease Research Center’s (WADRC) existing banked biofluids and phenotypic data to validate the 477 DMPs, including sites in B3GALT4 and ZADH2, as biomarkers of LOAD, while at the same time examining DNA methylation levels across the entire human genome (>25 million loci), with the potential to further identify novel DNA methylation predictors of LOAD. In addition, these studies will be expanded by examining a second cohort of female and male participants presently enrolled in the WADRC with and without mild cognitive impairment (MCI) to identify DNA methylation biomarkers prior to the onset of LOAD. MCI is an intermediate stage between cognitively normal older adults and LOAD. Patients with MCI have an elevated risk of progressing to dementia. Eighty percent of MCI patients convert to LOAD after an average of 6 years. Blood biomarkers that distinguish patients with MCI who later progress to LOAD from those with MCI who do not progress to LOAD offer a substantial opportunity to improve the diagnosis and early intervention in patients with accelerated cognitive aging. Together, findings from the present proposal will provide the foundation for identifying DNA methylation profiles in blood that predict the expression and progression to LOAD, detect deviations from healthy cognitive trajectories, identify modifiable risk factors and interventions, and bolster research efforts with an epigenetic metric that integrates heritable and acquired variables that influence aging.

项目概要最近基于芯片的脑组织表观基因组范围关联研究 (EWAS) 报告了差异 DNA 已知和新认识的晚发散发性阿尔茨海默病（LOAD）基因的甲基化，从而强调 EWAS 在揭示与 LOAD 发病机制相关的新基因和途径方面的效用。作为研究供体大脑样本的替代方案，研究可获取的 DNA 甲基化最近，我们发现外周组织提供了改善 LOAD 诊断和预后的机会。血液中的差异甲基化位置 (DMP) 可区分有或没有 LOAD 的男性和女性多个基因中的 769,190 个基因座中的 477 个在使用临床观察到的 DMP 之间共有 17 个。负载标记作为连续变量独立分析，包括雷伊听觉言语学习测试评分、脑脊液总 tau (t-tau) 和磷酸化 tau 181 (p-tau181) 水平以及 t-tau/Aβ1–42 (Aβ42)， p-tau181/Aβ42 和 Aβ42/Aβ1-40 (Aβ40) 比率在 LOAD 患者中，共有 17 个 DMP 中的 12 个低。 B3GALT4（β-1,3-半乳糖基转移酶 4）甲基化，该基因先前与上等动物中的 LOAD 相关颞回脑组织中，有 5 个在 ZADH2（前列腺素还原酶 3）中低甲基化，ZADH2 是一种新型 LOAD- 这些数据共同强化了利用血液来识别与痴呆相关的 DMP 由 LOAD 产生，导致假设血液中的 DNA 甲基化水平可用于识别新的使用基于全基因组的方法来确定 LOAD 的诊断、预后和可修改的治疗目标。该提案以威斯康星州阿尔茨海默病研究中心 (WADRC) 现有的数据库为基础生物流体和表型数据验证 477 个 DMP（包括 B3GALT4 和 ZADH2 中的位点）作为生物标志物 LOAD，同时检查整个人类基因组的 DNA 甲基化水平（>25 万个位点），有可能进一步识别 LOAD 的新 DNA 甲基化预测因子。通过检查目前参加该项目的第二组女性和男性参与者，将扩大研究范围 WADRC 有或没有轻度认知障碍 (MCI)，可在治疗前识别 DNA 甲基化生物标志物 MCI 的发病是认知正常的老年人和 LOAD 患者之间的中间阶段。 MCI 进展为痴呆的风险较高，百分之八十的 MCI 患者在接受 LOAD 治疗后会转变为 LOAD。平均 6 年的血液生物标志物可将 MCI 患者与后来进展为 LOAD 的患者区分开来。未进展至 LOAD 的 MCI 患者提供了改善诊断和早期诊断的重要机会总之，本提案的研究结果将提供对认知加速老化患者的干预。为识别血液中的 DNA 甲基化谱奠定基础，从而预测 DNA 的表达和进展负载，检测与健康认知轨迹的偏差，识别可改变的风险因素和干预措施，以及通过表观遗传指标来促进研究工作，该指标整合了影响遗传和后天的变量老化。