KIAA0319 modulates Alzheimer’s disease risk through PMM2 regulation: Evidence from integrated pQTL-mediation and transcriptomic analyses

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. 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 KIAA0319 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).