Cognitive impairment in age-related hearing loss: linking brain structure, glymphatic function, and molecular mechanisms

The neurobiological mechanisms of cognitive impairment in age-related hearing loss (ARHL) remain unclear. This study examined multi-level neural mechanisms from macroscale gray matter (GM) structure, microscale glymphatic function, and imaging transcriptomics. Sixty-nine ARHL patients and 76 controls underwent multimodal MRI and neuropsychological assessments. Glymphatic function was assessed via DTI-ALPS index and choroid plexus volume (CPV). Transcriptomic analysis using Allen Human Brain Atlas identified molecular pathways and key genes linked to GM atrophy. ARHL patients showed GM atrophy in right amygdala, left inferior frontal gyrus, and orbitofrontal cortex (OFC), but increased volume in left cerebellum. They also exhibited reduced ALPS index and enlarged CPV. Mediation analysis showed a significant indirect effect of glymphatic function on visual memory via right amygdala volume. Transcriptomics revealed enrichment in axonogenesis, energy metabolism, and protein ubiquitination, with key drivers including SMURF1 and GAD1. ARHL-related cognitive decline may follow a cascade from sensory deprivation to glymphatic dysfunction, involving energy metabolism, protein homeostasis, and axonal remodeling, ultimately leading to degenerative atrophy and compensatory adaptation in specific brain networks.