The Auditory Brainstem Response Diagnoses Alzheimer-Like Disease in the 5xFAD Mouse Model

Early and accurate diagnosis of Alzheimer’s Disease (AD) will be key for effective personalized treatment plans (Cummings, 2023). Significant difficulties in auditory processing have been frequently reported in many patients with mild cognitive impairment (MCI), the prodromal form of AD (Tarawneh et al., 2022), making it an outstanding candidate as AD diagnostic biomarker. However, the efficiency of diagnosis with this parameter has not been explored. Here we show that when male mice with amyloidosis begin to show memory decline, changes in the auditory brainstem response (ABR) to clicks enable the reliable diagnosis of disease using a machine learning algorithm. Interpretation of the machine learning diagnosis revealed that the upper levels of the auditory pathway, including the inferior colliculus, were the probable sources of the defects. Histological analyses show that in these locations, neuroinflammation and plaque deposition temporally correlate with behavioral changes consistent with memory loss. While these findings are tempered by the caveat that they derive from amyloidosis mice, we propose that ABR measurements be evaluated as an additional rapid, low-cost, non-invasive biomarker to assist the diagnostic testing of early-stage AD. Significance Statement New disease modifying treatments for AD only work for a subset of patients and require precise disease staging. AD is highly correlated with both central auditory dysfunction and hearing loss, but these are not diagnostic. We find that characteristics of the passive auditory brainstem response test reliably diagnose the onset of memory decline in a mouse model of AD, correlating with the initiation of amyloid deposits and neuroinflammation in the upper auditory nuclei. We further highlight the role that one region, the inferior colliculus, plays in multi-sensory integration, speculating that dementia becomes evident when the plaque-burdened cortex is unable to compensate for the degradation of pre-conscious sensory processing.