Network Meta-Analysis of Cognitive Impairment and miRNA Expression in Alzheimer’s Disease Patients with Hearing Loss: A Systematic Review and Cross-Validation

Background: Age-related hearing loss (HL) is a significant independent risk factor for Alzheimer's disease (AD), yet the molecular mechanisms underlying this comorbidity and the comparative efficacy of hearing interventions on cognitive outcomes remain unclear. This study aims to integrate clinical evidence and molecular data to address these gaps. Objective:To conduct a systematic review and network meta-analysis (NMA) to: 1) compare the effects of hearing interventions on cognitive function in AD patients; 2) identify and rank key microRNAs (miRNAs) associated with AD-HL comorbidity; 3) explore heterogeneity sources; and 4) cross-validate findings with independent clinical sequencing data. Methods: We systematically searched PubMed, Web of Science, Embase, and Cochrane Library up to May 2025. Included studies involved AD patients with/without HL, re-porting cognitive scores (MoCA, MMSE, AVLT) or miRNA expression data. A NMA was performed to rank interventions (cochlear implants-CI, hearing aids-HA, no in-tervention-NI) and miRNAs using surface under the cumulative ranking (SUCRA) curves. Heterogeneity was assessed via subgroup analysis and meta-regression. Pooled miRNA expression results were cross-validated against an independent clinical se-quencing dataset (LC-P20240110033, n=16) using intraclass correlation coefficient (ICC) and Bland-Altman plots. Results: Twelve studies (2,137 patients) were included. HL was significantly associated with worse cognitive function (MoCA: SMD = -0.82, 95% CI: -1.15 to -0.49; AVLT delayed recall: SMD = -1.12, 95% CI: -1.56 to -0.68). NMA revealed CI (SUCRA=0.89) was superior to HA (SUCRA=0.62) and NI (SUCRA=0.09) for preserving MoCA scores. Among nine differentially expressed miRNAs, hsa-miR-6875-5p was the most consistent biomarker (pooled FC = 1.52, 95% CI: 1.04–2.23), showing excellent agreement with sequencing data (FC = 3.29; ICC = 0.82, 95% CI: 0.67–0.91). Heterogeneity was significantly influenced by miRNA detection platform (p=0.04) and HL severity (p=0.03).Conclusion: This study demonstrates that HL exacerbates cognitive decline in AD in a dose-dependent manner. Cochlear implants may offer superior cognitive protection compared to hearing aids. The consistently dysregulated hsa-miR-6875-5p emerges as a promising cross-modal biomarker, bridging clinical observation and molecular pathology in AD-HL comor-bidity.