Abnormal Hearing Phenotypes in "Ignorome" Knockout Mice as Predictors of Cognitive Dysfunction.

Abstract

Alzheimer's disease and related dementias affect over 55 million people worldwide and are one of the most pressing public health challenges. Age-related hearing loss has emerged as a strong predictor of Alzheimer's disease and related dementias risk, raising the possibility that auditory dysfunction may serve as an early biomarker. While the causal nature of the relationship remains uncertain, treating hearing loss, or addressing a shared underlying mechanism, may improve quality of life and slow symptom progression in at-risk individuals. Current animal models of Alzheimer's disease largely focus on rare familial mutations, limiting their ability to capture the genetic and phenotypic heterogeneity of late-onset disease. To explore broader genetic contributions and potential links between hearing and cognition, we leveraged data from the International Mouse Phenotyping Consortium, a large-scale resource that provides standardized phenotyping across thousands of knockout mouse lines. Genes with abnormal auditory phenotypes were more likely to display behavioral abnormalities compared to genes without auditory involvement. Although other sensory modalities such as vision also showed associations with behavioral traits, the links to auditory dysfunction were stronger. Furthermore, higher auditory brainstem response thresholds correlated with the number of behavioral abnormalities across genotypes. Gene Ontology enrichment analyses of genes with auditory and behavioral phenotypes revealed distinct biological processes potentially linking sensory decline and cognitive vulnerability. These findings highlight candidate genes and molecular pathways connecting age-related hearing loss and Alzheimer's disease and related dementias, provide alternative genetic models that better reflect disease complexity, and suggest new avenues for early detection and intervention.