Network Meta-Analysis of Cognitive Impairment and miRNA Expression in Alzheimer's Disease Patients with Hearing Loss:...

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 for cognitive outcomes remain unclear. This study aims to integrate clinical evidence and molecular data to address these gaps. Objective: The objective of this study was to conduct a systematic review and network meta-analysis (NMA) in order 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 internal clinical sequencing data. Methods: We systematically searched PubMed, Web of Science, Embase, and the Cochrane Library, with a cut-off date of May 2024. Included studies involved AD patients with/without HL, reporting cognitive scores (MoCA, MMSE, and AVLT) or miRNA expression data. An NMA was performed to rank interventions (cochlear implants-CIs, hearing aids-HAs, and no intervention-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 internal clinical sequencing dataset (LC-P20240110033, n = 16) using the intraclass correlation coefficient (ICC) and Bland-Altman plots. Results: Twelve studies (2137 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 that the CI group (SUCRA = 0.89) was superior to the HA group (SUCRA = 0.62) and NI (SUCRA = 0.09) for preserving MoCA scores. Among the nine differentially expressed miRNAs identified in exploratory synthesis, three met strict quantitative criteria for NMA (reported in ≥2 independent studies with comparable quantification and variance data); 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 the miRNA detection platform (p = 0.04) and HL severity (p = 0.03). Conclusions: 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 hypothesis-generating cross-modal biomarker, bridging clinical observation and molecular pathology in AD-HL comorbidity.