Introduction: The incidence of depression in adolescents is increasing and is associated with severe cognitive impairment. This paper aimed to investigate the relationship between polymorphisms in microRNA-146a-5p (miR-146a-5p) and cognitive impairment in adolescent depression patients. Methods: Quantitative real-time polymerase chain reaction was used to quantify miR-146a-5p in serum. Detection of miR-146a-5p gene polymorphism was performed by TaqMan SNP Genotyping Assay. Odds ratios and 95% confidence intervals (CIs) were calculated by chi-square test (χ2) and logistic regression analysis. Results: Genotyping of miR-146a rs2910164 showed that CC (OR = 0.443, 95% CI, 0.264–0.741, p = 0.002) and GC (OR = 0.445, 95% CI, 0.279–0.712, p = 0.001) genotype reduced the risk of cognitive impairment in adolescent depression. The C allele (OR = 0.794, 95% CI, 0.694–0.741, p = 0.001) was a protective factor for cognitive impairment in adolescent depression compared to the rs2910164 G allele. Rs2910164 (OR = 0.425, 95% CI = 0.273–0.662, p = 0.000) showed a negative correlation with adolescents with cognitive impairment in depression by logistic regression analysis. The level of miR-146a-5p was decreased in carriers of the CC and CG genotypes. Conclusion: Rs2910164 C allele carriers have a low risk of cognitive impairment in adolescent depression and could reduce miR-146a-5p level.

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