Lukacsovich David, Young Juan I, Gomez Lissette, Schmidt Michael A, Zhang Wei, Kunkle Brian W, Chen X Steven, Martin Eden R, Wang Lily
Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
Dr. John T Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.
medRxiv. 2025 Jun 18:2025.06.17.25329345. doi: 10.1101/2025.06.17.25329345.
Aging is the strongest risk factor for Alzheimer's disease (AD), yet the molecular mechanisms linking aging to AD remain poorly understood. DNA methylation (DNAm) is an epigenetic modification that plays a critical role in gene regulation and has been implicated in both aging and AD. In this study, we performed a meta-analysis of DNAm profiles in the prefrontal cortex using two large, independent postmortem brain cohorts, the Religious Orders Study and Memory and Aging Project (ROSMAP) and Brains for Dementia Research (BDR), to identify DNAm differences associated with aging in late life. We identified 3,264 CpGs significantly associated with aging, the majority of which were hypermethylated and enriched in promoter regions and CpG islands. These aging-associated DNAm changes were significantly overrepresented in genes involved in immune regulation and metabolic pathways. When compared with AD-associated DNAm changes, we found a significant overlap, with nearly all CpGs and differentially methylated regions (DMRs) that were associated with both aging and AD Braak stage displaying concordant directionality. This supports the hypothesis that aging and AD are interconnected at the molecular level. Further integrative analyses indicated that a number of these DNAm variants may have functional relevance in AD. By integrating blood DNAm data, we identified multiple CpGs that showed significant brain-to-blood correlations and were involved in both aging and AD pathogenesis. Co-localization analyses with genome-wide association study (GWAS) data revealed shared genetic regulation of DNAm and dementia at several AD risk loci. Out-of-sample validation using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrated that, among 334 CpGs showing concordant DNAm changes in aging and AD, baseline DNAm levels at cg10752406 in the promoter were significantly associated with AD progression at a 5% false discovery rate, even after adjusting for age, sex, ε4 allele status, years of education, and baseline MMSE. Notably, this CpG also showed a strong brain-blood DNAm correlation, further supporting its potential as a peripheral biomarker for AD. Our study provides valuable insights into the epigenetic landscape of aging and its implications for AD, suggesting that aging-related epigenetic modifications may provide a viable source of biomarkers for AD.
衰老为阿尔茨海默病（AD）的最强风险因素，但衰老与AD之间的分子机制仍知之甚少。DNA甲基化（DNAm）是一种表观遗传修饰，在基因调控中起关键作用，且与衰老和AD均有关联。在本研究中，我们使用两个大型独立的死后大脑队列，即宗教团体研究与记忆和衰老项目（ROSMAP）以及痴呆症研究大脑库（BDR），对前额叶皮质中的DNAm图谱进行了荟萃分析，以识别与晚年衰老相关的DNAm差异。我们鉴定出3264个与衰老显著相关的CpG，其中大多数发生了高甲基化，且在启动子区域和CpG岛中富集。这些与衰老相关的DNAm变化在参与免疫调节和代谢途径的基因中显著过度富集。与AD相关的DNAm变化相比，我们发现有显著重叠，几乎所有与衰老和AD Braak分期均相关的CpG和差异甲基化区域（DMR）都显示出一致的方向性。这支持了衰老和AD在分子水平上相互关联的假说。进一步的综合分析表明，这些DNAm变异中的许多可能在AD中具有功能相关性。通过整合血液DNAm数据，我们鉴定出多个显示出显著脑血相关性且参与衰老和AD发病机制的CpG。与全基因组关联研究（GWAS）数据的共定位分析揭示了在几个AD风险位点上DNAm和痴呆症存在共同的遗传调控。使用阿尔茨海默病神经影像倡议（ADNI）数据集进行的样本外验证表明，在334个在衰老和AD中显示出一致DNAm变化的CpG中，即使在调整了年龄、性别、ε4等位基因状态、受教育年限和基线简易精神状态检查表（MMSE）后，启动子中cg10752406处的基线DNAm水平在5%的错误发现率下与AD进展显著相关。值得注意的是，这个CpG还显示出很强的脑血DNAm相关性，进一步支持了其作为AD外周生物标志物的潜力。我们的研究为衰老的表观遗传格局及其对AD的影响提供了有价值的见解，表明与衰老相关的表观遗传修饰可能为AD提供可行的生物标志物来源。
