Temporal progression of auditory brainstem dysfunction and behavioral phenotypes in mouse models of tauopathy

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Cognitive decline in Alzheimer's disease and related dementias (AD/ADRD) frequently co-occurs with motor and sensory processing impairments. While auditory abnormalities were reported in beta-amyloid-based models before cognitive decline, the effects of tau pathology on auditory circuit function remain poorly understood. The PS19 mouse model expressing the P301S tau mutation exhibits tau pathology associated with frontotemporal dementia. When combined with the humanized ApoE ɛ4 allele, these mice show accelerated tau accumulation and neurodegeneration. We investigated the temporal progression of auditory and behavioral deficits in PS19 and ApoE4/PS19 mice of either sex at 3 and 7 months. Auditory processing was assessed using auditory brainstem response (ABR) recordings, while anxiety-like and motor behaviors were evaluated using the elevated plus maze (EPM) and rotarod assays. PS19 mice exhibited auditory pathway dysfunction at 3 months, characterized by reduced and delayed neural responses to acoustic stimuli. These auditory deficits occurred without detectable behavioral changes in anxiety- or motor-related measures. By 7 months, cochlear-nucleus-derived ABR activity shifted from an initial reduction to elevation relative to controls, suggesting compensatory hyperexcitability. In contrast, ApoE4/PS19 mice showed reduced ABR amplitudes and shortened response latencies that persisted with age, accompanied by altered anxiety-like behavior and motor performance. Together, these results demonstrate that auditory pathway dysfunction may represent an early marker of tau pathology preceding behavioral impairment. The divergent temporal patterns of ABR alterations across genotypes suggest that genetic context, particularly ApoE4, modulates the progression of tau-driven circuit dysfunction, highlighting ABR as a potential noninvasive biomarker for early tau-related neurodegenerative disease. Significance Statement Early detection of Alzheimer's disease and related dementias remains a major clinical challenge. This study identifies auditory pathway dysfunction as an early, measurable marker of tau pathology, preceding detectable behavioral impairments in mouse models with abnormal auditory brainstem responses (ABRs) appeared months before anxiety or motor behavioral changes. Genetic background also significantly influenced disease progression, with the ApoE4 allele altering both the timing and nature of auditory and behavioral phenotypes. Together, these findings demonstrate that tau pathology disrupts auditory processing at early disease stages and suggest that ABR-based measures as sensitive, non-invasive approach for early detection and monitoring of tau-related neurodegeneration.

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