Auditory nerve phenotypes reveal a myelin-associated subtype of age-related hearing loss

Abstract

Communication difficulties in older adults are only partially explained by elevated hearing thresholds, suggesting that age-related changes in auditory nerve function contribute to disability beyond conventional measures of hearing sensitivity. Myelin degeneration is increasingly recognized as a fundamental feature of neural aging, yet its contribution to auditory nerve dysfunction remains poorly understood because validated in vivo biomarkers are lacking. We developed a normative physiological phenotyping framework by modeling the relationship between auditory nerve response amplitude and neural synchrony in younger adults and quantifying deviations from this relationship in older adults. Unsupervised clustering identified two auditory nerve phenotypes characterized by neural synchrony that was either as expected-or-better or poorer-than-expected relative to response amplitude, independent of age and hearing thresholds. The poorer-than-expected phenotype exhibited lower fractional anisotropy and higher radial and mean diffusivity in the auditory nerve, consistent with reduced myelin integrity. Human temporal bone diffusion MRI demonstrated changes in the same imaging metrics that corresponded with histological evidence of myelin degeneration, providing converging anatomical support for the imaging findings. Finally, the relationship between hearing loss and self-reported hearing difficulties differed between physiological phenotypes, demonstrating that poorer-than-expected neural synchrony amplifies the functional consequences of hearing loss. Together, these findings establish a physiologically defined, histologically validated biomarker of auditory nerve aging, implicate myelin degeneration as a previously underrecognized contributor to age-related communication difficulties, and introduce a general framework for identifying biologically meaningful neural aging phenotypes in living humans.