APOA1BP and natural killer cells as diagnostic and pathophysiological biomarkers in schizophrenia-associated cognitive impairment: A multi-cohort bioinformatics analysis

Schizophrenia (SZ) is frequently accompanied by cognitive impairment, yet validated molecular biomarkers remain limited. This study aimed to identify immune-related biomarkers, particularly APOA1BP and natural killer (NK) cells, through integrative bioinformatics analyses. Three gene expression omnibus transcriptomic datasets (GSE93987, GSE87610, GSE73129) were analyzed. Differentially expressed genes (DEGs) were identified and evaluated using Weighted Gene co-expression Network Analysis (WGCNA) and LASSO regression. Immune cell infiltration was assessed by single-sample gene set enrichment analysis (ssGSEA). Diagnostic performance of candidate genes was validated in independent cohorts using receiver operating characteristic analysis. Seventy DEGs were identified, mainly involved in extracellular matrix and cell adhesion. Four candidate genes (APOA1BP, C12orf57, MRPL46, ZDHHC11) were highlighted, with APOA1BP consistently downregulated in SZ. ROC analysis demonstrated diagnostic potential (AUC up to 0.76), though performance varied across tissues. NK cell infiltration was significantly elevated in SZ and negatively correlated with APOA1BP and MRPL46. Validation confirmed APOA1BP as the most robust biomarker in DLPFC-derived datasets, while olfactory epithelial-derived samples showed limited significance, likely reflecting tissue-specific heterogeneity. This multi-cohort bioinformatics analysis identifies APOA1BP and NK cells as promising biomarkers in SZ-associated cognitive impairment. While findings are correlative, they suggest that immune-metabolic interactions may contribute to SZ pathophysiology. Future research should validate these biomarkers in larger, clinically annotated cohorts and explore their mechanistic and therapeutic potential.