Examination of the bidirectional relationship between hearing loss and Alzheimer Disease pathology

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ABSTRACT Recent epidemiological studies have revealed an association between aging-related hearing loss (ARHL) and Alzheimer Disease (AD). Both of these disorders deprive individuals of their quality of life and both are rapidly rising in prevalence, given the aging of our population. Therefore, it is critical that we understand how AD and ARHL are related and whether this relationship can be used as leverage to better understand and treat both disorders. One key question is whether ARHL and AD are linked because of common risk factors or whether there is a causal relationship between the two (i.e., does ARHL exacerbate AD pathology?). This question cannot be answered effectively in human subjects because of the inability to independently manipulate hearing loss. Therefore, in the current study, we employ two animal models of AD (a model of sporadic and a model of familial AD) and ask whether manipulation of the peripheral auditory system alters AD pathology. To do this, we employ a novel model of sporadic AD that is based on cell-cycle dysregulation – a phenomenon that is commonly observed in brain specimens from AD patients. These AD model mice therefore do not carry a specific mutation in a gene that directly processes amyloid beta or tau. Nevertheless, they have been shown to display characteristic plaques and tangles, similar to what is seen in the AD brain, and neurodegeneration, which is not seen in most other mouse models of sporadic AD. The model of familial AD that will be used is the APP/PS1 mouse because it has been shown to display central auditory dysfunction and has a time course of pathology that matches with our sporadic AD model. In Aim 1, we will test both peripheral and central auditory function in these mice and hypothesize that, like AD patients, they will have more impairment in central, compared to peripheral, auditory function. In Aim 2, we will induce hearing loss and examine for exacerbation of AD pathology and induction of a progressive neurodegenerative phenotype using a combination of serial FDG PET imaging and behavioral analyses. We hypothesize that hearing loss will worsen AD pathology and exploratory analyses will be done to determine if changes are more severe in central auditory compared to non-auditory regions. Successful completion of this work will, for the first time, determine the nature of the association between hearing loss and AD pathology. If a causal association is found, future work will determine the molecular mechanisms of this association and whether mitigation of ARHL also diminishes AD pathology. Given the advancing pace of successful interventions for ARHL (aural rehabilitation, “smart” hearing aids, cochlear implants, etc.), this research could lay the groundwork for early intervention for ARHL to diminish the burden of dementia.