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bioRxiv · 10.64898/2026.05.25.727095

Alzheimer disease beta-amyloid pathology accelerates age-related hearing loss: evidence from AppNL-F 'knock-in' mice

Fuentes-Santamaria, V.·Alvarado, J. C.·Benitez, Z.·Gabaldon-Ull, M. C.·Sado, T. C.·Saito, T.·Lenarz, T.·Juiz, J. M.
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Abstract

Age-related hearing loss (ARHL) is a main acquired risk factor for dementia, including Alzheimer disease (AD), but links are unknown. We are using a mouse model with traits of both aging pathologies to test mechanistic interactions. The "knock-in" AppNL-F mouse reproduces {beta}-amyloid pathology in brain regions homologous to those involved in human AD. Because it was generated from the C57BL/6J mouse, it expresses early signs of ARHL, previously reported in this inbred strain. We found evidence that the early-onset ARHL of the C57BL/6J mouse is accelerated in the AppNL-F mouse. In adult C57BL/6J mice around seven-month-old, there were significant increases in auditory thresholds. In adult age-matched AppNL-F mice, auditory thresholds were significantly more elevated, suggesting acceleration of ARHL. In old mice, past thirteen months of age, hearing thresholds were equally elevated in both strains. Outer hair cell loss was significantly increased in adult AppNL-F relative to age-matched C57BL/6J mice, progressing from basal to apical cochlear turns. Spiral ganglion neuron loss also was larger. In adult AppNL-F mice there was more atrophy and enlarged capillary lumen size in the stria vascularis (SV), supporting accelerated ARHL. These findings suggest that central {beta}-amyloid pathology worsens age-related damage to the auditory receptor, thus accelerating ARHL. Damage to the SV and its capillaries in AppNL-F mice point to exacerbation of strial and vascular pathology in the aging cochlea by central {beta}-amyloid pathology. ARHL acceleration by central {beta}-amyloid pathology may contribute to a vicious circle with implications for prevention and therapies. HighlightsO_LIAge-related hearing loss worsens in a mouse model of Alzheimer {beta}-amyloid pathology. C_LIO_LIHearing thresholds further increase relative to naturally occurring hearing loss. C_LIO_LILoss of outer hair cells and spiral ganglion neurons is larger. C_LIO_LIThe stria vascularis and its microcirculation are more atrophic and damaged. C_LIO_LIAlzheimer disease may potentiate peripheral presbycusis. C_LI

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Fuentes-Santamaria, V., Alvarado, J. C., Benitez, Z., Gabaldon-Ull, M. C., Sado, T. C., Saito, T., Lenarz, T., Juiz, J. M.. 2026-05-28. Alzheimer disease beta-amyloid pathology accelerates age-related hearing loss: evidence from AppNL-F 'knock-in' mice. https://doi.org/10.64898/2026.05.25.727095

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