Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease

Yudi Xu; Shutong Liu; Zhaokai Zhou; Hongzhuo Qin; Yuyuan Zhang; Ge Zhang; Hongxuan Ma; Xinwei Han; Huimin Liu; Zaoqu Liu

doi:10.1093/hmg/ddae189

Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer's disease

Hum Mol Genet. 2024 Dec 18:ddae189. doi: 10.1093/hmg/ddae189. Online ahead of print.

Authors

Yudi Xu¹, Shutong Liu², Zhaokai Zhou³, Hongzhuo Qin¹, Yuyuan Zhang², Ge Zhang⁴, Hongxuan Ma⁵, Xinwei Han^{2

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7}, Huimin Liu¹, Zaoqu Liu^{2

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8}

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
² Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
³ Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
⁴ Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
⁵ Department of Kidney Transportation, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
⁶ Interventional Institute of Zhengzhou University, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
⁷ Interventional Treatment and Clinical Research Center of Henan Province, No. 1 Jianshe Dong Road, ErQi District, Zhengzhou, Henan 450052, China.
⁸ Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Dongcheng District, Beijing 100730, China.

PMID: 39690817
DOI: 10.1093/hmg/ddae189

Abstract

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.

Keywords: Alzheimer’s disease; cellular senescence; genome-wide association studies; integrative omics.

Grants and funding

221100310100/Science and Technology Department of Henan