Integrated clinical and transcriptomic analysis reveals miRNA-mediated mechanisms linking hearing loss to cognitive decline in Alzheimer's disease

BackgroundHearing loss (HL) is a potent, modifiable risk factor for Alzheimer's disease (AD), but the underlying molecular mechanisms remain elusive. microRNAs (miRNAs) are potential key mediators given their roles in both neurodegeneration and auditory function.ObjectiveTo investigate whether peripheral blood miRNA profiles differ between AD patients with and without HL, and whether hsa-miR-6875-5p serves as a candidate molecular link.MethodsIn a case-control study of 41 AD patients (AD-HL n = 24, AD-non-HL n = 17), we performed neuropsychological assessments, plasma miRNA sequencing, target gene prediction, and external validation using public transcriptomic datasets.ResultsAD-HL patients showed significantly worse Montreal Cognitive Assessment and Auditory Verbal Learning Test delayed recall scores (p < 0.05). We identified 9 differentially expressed miRNAs, with hsa-miR-6875-5p being the most upregulated (3.29-fold, p = 0.041). Its predicted targets were enriched in synaptic plasticity-related pathways. External validation in AD brain datasets supported consistent upregulation of hsa-miR-6875-5p and downregulation of SYN1/PSD95. Validation in mouse cochlear datasets showed concordant expression trends for homologous miRNA and target genes. The absence of healthy control groups precludes determination of whether this miRNA signature is specific to AD-HL or a general feature of HL or AD.ConclusionsThis preliminary study identifies hsa-miR-6875-5p as a potential circulating biomarker linking HL to cognitive decline in AD. These findings are hypothesis-generating and require confirmation in larger cohorts, including healthy controls, and functional experiments.