Emerging evidence implicates exosomes in the pathogenesis of Alzheimer's disease (AD).
Objective
This study aimed to investigate the role of exosome-related genes in AD pathogenesis and evaluate their potential as diagnostic biomarkers.
Methods
We analyzed AD transcriptomic datasets (GSE5281, GSE138260, GSE29378) from the Gene Expression Omnibus database. Exosome-related differentially expressed genes (DEGs) were identified by intersecting the DEGs with exosome-related genes derived from GeneCards. The most AD-relevant exosome-related DEGs were screened using the least absolute shrinkage and selection operator regression and random forest algorithms. We then performed a two-sample Mendelian randomization (MR) analysis to evaluate potential causal effects of these candidate genes on AD risk, with the inverse-variance weighted method as the primary approach. Underlying molecular mechanisms were investigated through gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA). The diagnostic potential of candidate genes was assessed via external validation.
Results
Four core exosome-related DEGs (TGFBR3, CXCR4, PSMB3, CD44) were identified. MR analysis demonstrated a significant causal effect of elevated TGFBR3 expression on AD risk (OR = 1.885, 95% CI 1.091–3.255, p = 0.023). Integrated GSEA and GSVA linked high TGFBR3 expression to synaptic impairment. Notably, TGFBR3 exhibited robust diagnostic accuracy across multiple external validation cohorts.
Conclusions
TGFBR3, an exosome-related gene, may contribute to AD pathogenesis via synaptic dysfunction. Our findings support its potential as a diagnostic biomarker for AD.
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