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

Dec 18, 2024Human molecular genetics

Molecular networks and possible targets of cell aging in Alzheimer's disease revealed by combined multi-omics analysis

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Abstract

Cellular senescence levels in Alzheimer's disease are higher compared to healthy controls.

Higher levels of cellular senescence are observed in Alzheimer's disease compared to healthy individuals.
A total of 113 cellular senescence-related genes were identified in blood, and 410 in brain tissue as potential candidates involved in Alzheimer's disease.
An integrative mendelian randomization analysis identified five putative Alzheimer's disease-causal genes and 18 DNA methylation probes linked to them.
Integrative analysis revealed two additional genes and 12 regulatory elements associated with Alzheimer's disease.
In brain tissue, two genes were prioritized as potential causal genes and validated through laboratory experiments.

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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.

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

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