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

• 批准号: 10398174
• 负责人: Reid Spencer Alisch
• 金额: $ 61.98万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10398174
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' 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; Persons; Phenotype; Population; Positioning Attribute; Prognosis; 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; disease prognosis; 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; phenotypic biomarker; phenotypic data; primary care setting; prognostic; tau Proteins; tau-1; therapeutic target; whole genome

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.

项目摘要 脑组织的最近基于阵列的表观基因组结合研究（EWAS）报告了差异DNA 甲基化已知和新认可的晚期发病的阿尔茨海默氏病（负载）基因，从而 强调EWAS在披露与负载发病机理相关的新基因和途径方面的效用。 作为研究供体大脑样品的研究的替代方案，研究了可访问的DNA甲基化 外围组织提供了改善负载诊断和预后的机会。最近，我们已经确定了 血液中有不同的甲基化位置（DMP），以区分有和没有负载的男性和女性 在多个基因中的769,190个地方中的477个。在这些DMP中，使用临床观察到的DMP之间共享17个 负载标记物被独立分析，因为连续变量完成了REY听觉口头学习测试 评分，脑脊液总TAU（T-TAU）和磷酸化的TAU 181（P-TAU181）水平，T-TAU/Aβ1-42（Aβ42）， P-TAU181/Aβ42和Aβ42/Aβ1-40（Aβ40）比率。在负载患者中，共有17个DMP中有12例是低压 在B3GALT4（β-1,3-糖基转移酶4）中甲基化，该基因先前与上载中的载荷相关 在ZADH2（前列腺素还原酶3）中，暂时的回脑组织和5个是甲基化的，这是一种新型的负荷 - 相关基因。这些数据共同加强了使用血液来识别与痴呆相关的DMP 由负载产生，导致假说，即血液中的DNA甲基化水平可用于鉴定新型 诊断，预后和可修改的负载治疗靶标。使用基于全基因组的方法， 该提案建立在威斯康星州阿尔茨海默氏病研究中心（WADRC）现有的基础上 生物流体和表型数据以验证477 DMP，包括B3GALT4和ZADH2中的位点，作为生物标志物 负载，同时检查整个人类基因组中的DNA甲基化水平（> 25 百万个局部），有可能进一步识别负载的新型DNA甲基化预测指标。另外，这些 研究将通过检查第二名的女性和男性参与者来扩展研究 WADRC有和没有轻度认知障碍（MCI），以鉴定DNA甲基化生物标志物 负载发作。 MCI是认知正常的老年人和负载之间的中间阶段。患者 MCI患痴呆症的风险较高。 80％的MCI患者在 平均6年。血液生物标志物与MCI的患者区分开来，后来又会加载这些患者 与不进行负载的MCI一起提供了大量机会来改善诊断和尽早 干预加速认知衰老的患者。本提案的发现将共同提供 鉴定血液中DNA甲基化谱的基础，以预测表达和进展 负载，检测与健康的认知轨迹不同，确定可修改的危险因素和干预措施以及 通过表观遗传指标来巩固研究工作 老化。