Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: This integrative analysis uncovered a novel KIAA0319-PMM2 regulatory axis implicated in AD pathogenesis. Both proteins represent potential therapeutic targets for future AD interventions.