Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer’s disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants. In this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with a P value cutoff of 1 × 10−5 to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g., BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex). Our work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.

中文翻译：

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利用阿尔茨海默病神经影像计划 (ADNI) 中的外周 DNA 甲基化差异来揭示疾病的新生物标志物。

阿尔茨海默病 (AD) 是一种慢性进行性神经退行性疾病，影响全球约 4400 万成年人。AD 的因果病理学（β-淀粉样蛋白和 tau 蛋白的积累）比痴呆症的标志性症状早十多年，因此需要开发疾病发作的早期诊断标记物，特别是旨在改变疾病过程的新药。为了评估差异甲基化位置 (DMP) 作为 AD 的新型血液生物标志物，我们使用了阿尔茨海默病神经影像倡议 (ADNI) 联盟中 653 名个体的外周血 (PB) 样本。选定的 AD、轻度认知障碍 (MCI) 和年龄匹配的健康对照 (CN) 队列均具有影像学、遗传学、转录组学、脑脊蛋白标记物和全面的临床记录，提供了丰富的并发多组学和表型资源有关 ADNI 参与者的良好表型子集的信息。在这篇手稿中，我们报告了一组 AD、MCI 和年龄匹配的 CN 个体的交叉诊断差异外周 DNA 甲基化，并进行了纵向 DNA 甲基化测量。表观基因组范围的关联研究 (EWAS) 使用混合模型进行，随着时间的推移重复测量，P 值截止值为 1 × 10−5，以测试 AD 与 CN、AD 与 MCI 以及 MCI 与CN. 最显着的差异甲基化位点还通过简易精神状态检查（MMSE）分数进行追踪。差异甲基化位点在大脑附近富集，并且使用基因型组织表达项目门户网站 (GTex) 验证了神经退行性相关基因（例如 BDNF、BIN1、APOC1）。我们的工作表明，年龄匹配的 AD 受试者相对于健康对照之间的外周差异甲基化将为进一步研究和验证差异甲基化作为疾病的替代物提供机会。鉴于脑组织难以接近，PB 相关的甲基化标记可能有助于识别疾病的阶段和进展表型，这些信息对于开发成功治疗 AD 的药物至关重要。