To investigate whether genetic susceptibility to intravenous anesthesia exposure affects
the risk of postoperative cognitive dysfunction (POCD) and whether cerebrospinal fluid N-acetylarginine plays a
mediating role in this association. Methods: Two-sample, two-step Mendelian randomization (TSMR) analysis
was conducted using genome-wide association study (GWAS) summary statistics primarily from cohorts of
European ancestry. First, we examined the genetic susceptibility of cerebrospinal fluid metabolites to intravenous
anesthetic agents. Then, we evaluated the impact of these metabolites on cognitive outcomes as a surrogate
marker for POCD risk. The primary estimates were obtained through inverse variance-weighted MR,
supplemented by weighted median, MR-Egger, and mode-based methods. Robustness was assessed using
Cochran’s Q, MR-Egger intercept, MR-PRESSO (global/outlier), and Steiger directionality tests. The mediating
effect was measured by the product of coefficients, with uncertainty estimated via the delta method/
bootstrapping and multiple testing correction applied within the metabolome. Exploratory bioinformatics
integrated differentially expressed genes with protein-protein interaction (PPI)/gene ontology (GO)/Kyoto
Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Results: Genetic susceptibility to
intravenous anesthetic agents was associated with changes in cerebrospinal fluid N-acetylarginine levels, which,
in turn, were linked to an increased risk of POCD. This N-acetylarginine-mediated effect accounted for a
significant portion of the total effect. Colocalization and multivariable Mendelian randomization (MVMR)
confirmed metabolite-specific signals, and enrichment results indicated involvement of nitric oxide signaling and
interactions with the Notch pathway. Conclusion: TSMR revealed that cerebrospinal fluid N-acetylarginine
partially mediates the association between susceptibility to intravenous anesthetic agents and POCD risk.
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