Wen Peng, Han Chong, Zhao Hongxin, Yao Shengtao, Chen Huan
Department of Neurosurgery, The Third Affiliated Hospital of Zunyi Medical University, The First People's Hospital of Zunyi, Zunyi, China.
Department of Cerebrovascular Disease, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
J Alzheimers Dis Rep. 2025 Sep 29;9:25424823251384245. doi: 10.1177/25424823251384245. eCollection 2025 Jan-Dec.
Genome-wide studies have identified multiple risk genes for Alzheimer's disease (AD), yet the causal protein interactions and pathways driving AD pathogenesis remain unclear.
This study aimed to assess the causal relationships between plasma proteins and AD risk, and to delineate protein-mediated regulatory pathways involved in AD pathogenesis.
We assessed the causal relationships between plasma proteins and AD risk using protein quantitative trait loci (pQTL) data from two large-scale resources: the UK Biobank Pharma Proteomics Project (UKB-PPP) and deCODE genetics. These data were integrated with genome-wide association studies (GWAS) on AD. We applied two-sample Mendelian randomization (MR), followed by two-step MR and mediation analyses, to delineate causal regulatory pathways and quantify mediating effects of proteins in AD pathogenesis. To further provide supporting evidence, we analyzed transcriptomic data from postmortem AD brain tissues (GSE33000, Gene Expression Omnibus) and conducted differential expression analyses.
In the UK Biobank cohort, seven upstream proteins showed causal associations with six downstream proteins in the deCODE cohort, which in turn influenced AD risk through both positive and negative regulatory effects (p < 0.05). Transcriptomic analysis demonstrated significant downregulation of in AD patients (p < 0.0001). These findings were consistent with our mediation analysis, which indicated that reduced KIAA0319 expression adversely affected PMM2 and thereby increased AD risk (mediation effect: 13.37%, 95% CI: 1.68%-25.06%, p < 0.05).
This integrative analysis uncovered a novel KIAA0319-PMM2 regulatory axis implicated in AD pathogenesis. Both proteins represent potential therapeutic targets for future AD interventions.
全基因组研究已确定了阿尔茨海默病（AD）的多个风险基因，但驱动AD发病机制的因果蛋白相互作用和途径仍不清楚。
本研究旨在评估血浆蛋白与AD风险之间的因果关系，并描绘参与AD发病机制的蛋白介导的调控途径。
我们使用来自两个大规模资源的蛋白质定量性状位点（pQTL）数据评估血浆蛋白与AD风险之间的因果关系：英国生物银行药物蛋白质组学项目（UKB-PPP）和deCODE遗传学。这些数据与AD的全基因组关联研究（GWAS）相结合。我们应用两样本孟德尔随机化（MR），随后进行两步MR和中介分析，以描绘因果调控途径并量化蛋白在AD发病机制中的中介作用。为了进一步提供支持性证据，我们分析了死后AD脑组织的转录组数据（GSE33000，基因表达综合数据库）并进行了差异表达分析。
在英国生物银行队列中，七种上游蛋白与deCODE队列中的六种下游蛋白显示出因果关联，这些下游蛋白又通过正向和负向调控作用影响AD风险（p < 0.05）。转录组分析表明AD患者中 显著下调（p < 0.0001）。这些发现与我们的中介分析一致，中介分析表明KIAA0319表达降低对PMM2产生不利影响，从而增加AD风险（中介效应：13.37%，95%CI：1.68%-25.06%，p < 0.05）。
这种综合分析揭示了一个与AD发病机制相关的新的KIAA0319-PMM2调控轴。这两种蛋白均代表未来AD干预的潜在治疗靶点。
