5xFAD mutations induce hearing impairment in the Ahl-corrected 5xFAD mice

Age-related hearing impairment (ARHI) has been strongly associated with cognitive impairment in case-controlled and longitudinal population-based studies. However, a mechanistic link between ARHL and Alzheimer's disease (AD)-related dementia remains unclear. In this study, we developed Ahl-corrected C57BL/6-background 5xFAD mice (referred to as FAD2), an AD mouse model suitable for precise assessment of auditory function, along with their wildtype littermates (WT2). WT2 mice of both sexes exhibited stable auditory brainstem response (ABR) thresholds from 3-4 months to 9-10 months of age at frequencies of 8, 16, and 32 kHz. In contrast, FAD2 mice showed significant threshold elevations at 9-10 months, with greater impairment at higher frequencies and in females. Interestingly, both sexes of FAD2 mice at 3-4 months of age exhibited significantly elevated ABR suprathreshold wave I amplitudes at 32 kHz compared to WT2 mice at that age, suggesting early auditory nerve hyperexcitability. These amplitudes gradually declined by 9-10 months, with female FAD2 mice showing significantly lower values than WT2 mice. Notably, hearing impairments at 9-10 months were not associated with sensory hair cell loss or brain amyloid deposition but correlated with early wave I amplitude elevations. Degeneration of myelin in spiral ganglion neurons (SGNs) was observed in severely hearing-impaired FAD2 mice. Additionally, acoustic startle response (ASR) was significantly reduced at 6-7 months in FAD2 mice of both sexes. These findings suggest that 5xFAD mutations induce early auditory nerve hyperexcitability, leading to SGN degeneration and ARHL. Furthermore, the early ASR decline implies alteration in central nervous system circuits alterations, potentially marking early neurodegenerative changes.