Abstract
Age-related hearing loss was recently established as the largest modifiable risk factor for Alzheimer’s disease (AD), however, the reasons for this link remain unclear. We investigate shared underlying genetic associations using results from recent large genome-wide association studies (GWAS) on adult hearing difficulty and AD. Genetic correlation and Mendelian randomization (MR) analysis do not support a genetic correlation between the disorders, but suggest a direct causal link from AD genetic risk to hearing difficulty, driven by APOE. Systematic MR analyses on the effect of other traits revealed shared effects of glutamine, gamma-glutamylglutamine, and citrate levels on reduced risk of both hearing difficulty and AD. In addition, pathway analysis on GWAS risk variants suggests shared function in neuronal signalling pathways as well as etiology of diabetes and cardiovascular disease. However, after multiple testing corrections, neither analysis led to statistically significant associations. Altogether, our genetic-driven analysis suggests hearing difficulty and AD are linked by a shared vulnerability in molecular pathways rather than by a shared genetic architecture.
Highlights
Dementia and age-related hearing loss (ARHL) are two of the most common age-related diseases, affecting ~50 million and 466 million worldwide, respectively[1,2]
The results do not support a broad shared genome-wide genetic architecture between HDiff and Alzheimer’s disease (AD) that could explain the link between the two conditions
Results from MR analysis provide some evidence to suggest that AD causes greater hearing difficulty at the level of AD genetic risk variants
Summary
Dementia and age-related hearing loss (ARHL) are two of the most common age-related diseases, affecting ~50 million and 466 million worldwide, respectively[1,2] Both have a significant impact on the health and wellbeing of the ageing population[3,4,5] causing social isolation, higher healthcare costs, and currently have limited treatment options. ARHL or presbycusis is the most common form of sensory loss in older people and the third most common health condition in older adults after heart disease and arthritis[7]. It is characterized by bilateral hearing thresholds of >25 dB, often affecting the higher frequencies first before progressing to lower frequencies, as well as hearing difficulty with background noise[2,8]. The underlying pathological mechanisms responsible for ARHL are not well understood but are likely to involve a combination of pathologies acquired in different components of the highly complex auditory pathway
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