Circulating microRNAs and depressive symptom severity in older adults: evidence for an association with miR-29b-3p

Abstract Depressive symptoms in later life represent a major clinical concern because they are associated with cognitive decline, multimorbidity, and increased mortality among older adults. Although circulating microRNAs (miRNAs) emerged as potential biomarkers in major depressive disorder, their role in late-life depressive symptom severity remains poorly defined. In this study we investigated the association between plasma levels of three miRNAs involved in neuroinflammation and synaptic function (miR-23a-3p, miR-26a-5p, and miR-29b-3p) and depressive severity in a population of 123 community-dwelling subjects. Individuals aged 65–97 years were classified for depressive status according to the 15-item Geriatric Depression Scale (GDS-15), in addition to their cognitive function, functional and nutritional status, and multimorbidity. Analysis of covariance, adjusted for demographic, cognitive and clinical covariates, found that plasma levels of all three miRNAs progressively decreased with increasing depressive symptom severity and differed significantly across GDS-15 symptom severity categories, particularly between participants with moderate and higher depressive symptom burden. Among the investigated miRNAs, miR-29b-3p showed the strongest and most robust association, remaining significant after extensive covariate adjustment and false discovery rate correction. Analyses of predictive performance, evaluated by receiver operating characteristic (ROC) curve analysis, supported this association, showing that the inclusion of miR-29b-3p improved the discrimination of participants with more severe depressive symptoms within the study sample. Furthermore, higher miR-29b-3p levels were associated with better cognitive performance. MiR-23a-3p and miR-26a-5p were attenuated after adjustment and appeared to reflect broader aspects of aging and multimorbidity rather than depression-specific mechanisms. Pathway enrichment analysis of predicted miR-29b-3p targets identified pathways involved in cellular stress responses and metabolic regulation, including PI3K–Akt and FOXO signaling. In conclusion, miR-29b-3p emerged as a candidate circulating marker associated with depressive symptom severity and cognitive vulnerability in older adults.