Project Summary A link between hearing loss and dementia is well established from epidemiological studies; however, whether or not there is a causal link between hearing loss and dementia is unclear. The primary goal of the proposed research is to use Common Fund datasets to investigate common genetic mutations associated with hearing dysfunction and cognitive deficits. The proposed research extends the scope of the parent grant which focuses on characterizing the behavioral and physiological trajectory of hearing loss in three specific mouse models with gene mutations that result in brain pathologies mimicking certain aspects of Alzheimer’s and related dementias (ADRD) in humans. While these models are useful for investigating the potential contribution of specific predetermined pathological trajectories in hearing dysfunction, they do not adequately recapitulate human dementias, which may arise from a host of mechanisms and display varying cognitive-behavioral phenotypes. Identification of genetic factors that predispose a person to both hearing dysfunction and dementia is critical for developing more valid animal models and probing potential mechanisms to target with biomedical treatments. We hypothesize that abnormal cognition will be more prevalent in KO mice with hearing dysfunction compared to those without hearing dysfunction. Our research will address this knowledge gap through two Specific Aims that use Common Fund data to investigate additional genotype-phenotype relationships between hearing dysfunction and cognitive deficits: 1) Analyze correlations between hearing phenotypes and cognitive-emotional behavioral phenotypes in data from the Knockout Mouse Phenotyping Program (KOMP2) to identify common genetic mechanisms, and 2) Compare genes of interest identified in Aim 1 against publicly available data in the Human BioMolecular Atlas Program (HuBMAP) and other publicly available data repositories to determine which human tissues express these genes and which genes are known to be expressed in the peripheral and central auditory systems. Additionally, we will quantify the co-occurrence of hearing dysfunction, cognitive deficits, and anxiety, fear, or stress phenotypes. We will consider sex as a biological variable to determine if hearing dysfunction with cognitive phenotypes are more prevalent in males or females in the KOMP2 dataset. This work will inform future investigations linking the trajectory of hearing dysfunction with cognitive deficits, including ADRD, and provide potential targets for future preclinical studies investigating novel therapeutic interventions.

Project Narrative There is a significant gap in what we know about the causal link between hearing loss and Alzheimer’s Disease and related dementias. This study will use publicly available datasets to characterize the relationship between hearing dysfunction, other sensory dysfunction, and behavioral cognitive and emotional dysfunction in animal models to identify potential common genetic drivers of these phenotypes and provide new potential targets for therapies to prevent or ameliorate hearing loss and dementia.