Xu Yudi, Liu Shutong, Zhou Zhaokai, Qin Hongzhuo, Zhang Yuyuan, Zhang Ge, Ma Hongxuan, Han Xinwei, Liu Huimin, Liu Zaoqu
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
Hum Mol Genet. 2025 Feb 17;34(5):381-391. doi: 10.1093/hmg/ddae189.
Cellular senescence (CS) is a hallmark of Alzheimer's disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.
细胞衰老（CS）是阿尔茨海默病（AD）的一个标志。然而，CS导致AD发病机制仍知之甚少。我们发现，与健康对照组相比，AD患者的CS水平更高。基于转录组的差异表达分析确定了血液中113个与CS相关的基因和脑组织中410个作为参与AD的潜在候选基因。为了进一步探究这些基因的因果作用，我们进行了综合孟德尔随机化分析，将AD全基因组关联研究汇总统计数据与来自血液样本的表达数量性状位点（eQTL）和DNA甲基化数量性状位点（mQTL）数据相结合，确定了5个假定的AD因果基因（CENPW、EXOSC9、HSPB11、SLC44A2和SLFN12）以及18个相应的DNA甲基化探针。此外，对血液中的eQTL和mQTL进行综合分析，发现了两个与AD相关的基因和12个相应的调控元件。此外，两个基因（CDKN2B和ITGAV）被确定为脑组织中的假定因果基因，并通过体外实验得到验证。多组学整合研究揭示了遗传易感性驱动的CS在AD中的潜在作用和潜在生物学机制。本研究有助于从根本上理解CS在AD发病机制中的作用，并促进了AD预防和治疗潜在靶点的识别。
