The Genetic and Transcriptomic Nexus of Age-Related Hearing Loss and Alzheimer's Disease.

Introduction

Despite the recognized association between age-related hearing loss (ARHL) and Alzheimer's disease (AD), the genetic relationship and shared transcriptional mechanisms between them remain largely unexplored.

Methods

We systematically investigated the ARHL-AD axis using a multi-layered genomic strategy, incorporating causal inference, cis-eQTL mediation, Bayesian colocalization, and independent replication cohort validation.

Results

Genetically predicted ARHL was associated with a reduced risk of overall AD and its early/late-onset subtypes, with no evidence of reverse causality in reverse MR analyses. Among 36 identified mediating genes, CSK showed the most consistent mediation signals across discovery and replication cohorts, although the replication was statistically partial (Sobel p = 0.078). Pathway analyses revealed that these genetic links predominantly involve Wnt signaling and endoplasmic reticulum protein processing. Discussion: Our integrative multi-omics findings suggest a potential genetic association between ARHL liability and AD risk. More importantly, we identified a prioritized CSK-driven transcriptional network, providing novel mechanistic insights and highlighting a candidate gene for future functional investigation in neurodegeneration.