Objective: To identify and validate differential mRNA N6-methyladenosine (m6A) methylation sites associated with mild cognitive impairment (MCI), providing potential molecular evidence for its early prevention and intervention. Methods: A case-control study was conducted among older adults recruited from multiple community health centers in Shenzhen, including a pilot cohort (5 pairs) and a validation cohort (25 pairs). Single-based m6A quantitative polymerase chain reaction was used to quantify plasma mRNA m6A methylation levels. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed, followed by the construction of a protein-protein interaction network to identify hub genes. The differential methylation levels of key genes were validated in an expanded cohort. For normally distributed data, t-tests were used; for non-normal data, Mann-Whitney U or χ2 tests were applied. Partial correlation analysis and Firth logistic regression were conducted to verify the associations further. Results: A total of 126 differential mRNA m6A methylation sites were identified, including 73 upregulated and 53 downregulated sites. Five hub genes (ZFHX3, PARD3, ARHGEF2, GLB1, and LRIG3) were selected, based on protein-protein interaction network topology. Validation experiments showed that the mRNA m6A methylation levels of these five genes were significantly higher in the MCI group than in healthy controls (all P<0.001). After adjustment for potential confounders, partial correlation analysis revealed that the methylation levels of all five genes were negatively correlated with MMSE scores (r=-0.719- -0.426, all P<0.05). Firth logistic regression confirmed that these genes were independently associated with MCI (OR=1.57-2.88, all P<0.001). Conclusion: This study screened and verified a range of MCI-related differential m6A methylation sites, suggesting that abnormal m6A methylation of specific gene mRNAs may be associated with MCI, providing research clues for further exploration of the molecular mechanism of MCI and potential plasma molecular markers. 目的： 筛选并验证与轻度认知功能障碍（MCI）相关的差异mRNA N6-甲基腺苷（m6A）甲基化位点，为探索MCI的潜在分子特征提供依据。 方法： 采用病例对照设计，选取深圳市多中心社区健康体检老年人作为研究对象，分为预实验（5对）和验证实验（25对）。通过m6A单碱基定量聚合酶链式反应检测血浆mRNA m6A甲基化修饰水平，并进行基因本体论、基因组百科全书富集分析及构建蛋白互作网络以筛选关键基因；在验证实验中检验其甲基化差异，正态分布数据采用t检验，非正态检验采用Mann-Whitney U检验或χ2检验，通过偏相关分析及Firth logistic回归分析验证。 结果： 共筛选出126个差异mRNA m6A甲基化位点，其中上调73个，下调53个；基于蛋白互作网络分析筛选出5个关键基因（ZFHX3、PARD3、ARHGEF2、GLB1、LRIG3）。验证结果显示，MCI组各基因的mRNA m6A甲基化修饰水平均高于健康对照组（均P<0.001）。偏相关分析调整混杂因素后，各基因mRNA m6A甲基化修饰水平与简易精神状态检查表评分呈负相关（r=-0.719~-0.426，均P<0.05），Firth logistic回归分析显示，各基因均与MCI状态存在独立关联（OR=1.57~2.88，均P<0.001）。 结论： 研究筛选并验证了多种与MCI相关的差异mRNA m6A甲基化位点，提示特定基因mRNA的m6A修饰异常可能与MCI相关，为进一步探索MCI的分子机制及潜在血浆分子标志物提供了研究线索。.
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arXiv · 2026-03-05
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