Table_1_A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration.XLSX

Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.

阿尔茨海默病（Alzheimer's disease, AD）以脑内DNA甲基化（DNA methylation, DNAm）模式的特异性改变为核心特征。年龄与性别作为AD的两大主要危险因素，已知可显著调控脑内表观遗传谱，但二者对AD相关DNAm改变的贡献却长期未得到充分研究。本研究纳入了来自健康成人与AD患者的四个脑区（颞叶、额叶、内嗅皮层及小脑）的公开DNAm数据集，通过荟萃分析筛选与性别、年龄及AD相关的表观遗传谱。其中一个数据集还可区分5-甲基胞嘧啶（5-methylcytosine, 5mC）与5-羟甲基胞嘧啶（5-hydroxymethylcytosine, 5hmC）的修饰谱。研究结果显示，男女之间的DNAm差异在四个脑区中具有较高共通性，而衰老对皮层区域的影响模式与小脑存在显著差异。我们发现，同时受年龄调控且呈现性别依赖性的甲基化探针比例高于预期，但男女之间的甲基化差异整体得以维持，仅极少数探针表现出年龄-性别交互效应。本研究未发现AD相关探针与性别相关探针存在显著重叠，也未检测到疾病-性别交互效应。反之，AD相关的表观遗传修饰显著富集于随年龄变化的DNAm探针中，且衰老与AD中甲基化改变的方向（高甲基化或低甲基化）高度一致，提示该疾病伴随表观遗传衰老加速。综上，本研究结果表明，与年龄相关的DNAm模式参与了AD中出现的表观遗传失调，为高龄如何促进神经退行性变提供了全新的研究视角。