In this study, we utilized a two-sample MR method based on a large-scale GWAS database to explore the causal genetic relationship between ARHL and dementia, including Alzheimer's disease, vascular dementia, and Parkinson's dementia. The study showed no causal relationship between ARHL and the risk of common dementias discussed in this paper.In recent years, there has been increasing interest in the relationship between ARHL and dementia, with one observational study suggesting a potential association between ARHL and dementia [25]. In an assessment of the prevalence of cognitive impairment in individuals with ARHL over the age of 65, mild cognitive impairment was significantly associated with hearing impairment. In another study[26], 1057 men were followed for 17 years to assess cognitive outcomes. The study found that dementia and cognitive decline were associated with auditory thresholds over the 17-year period. Hearing loss has been found to be associated with a greater risk of developing dementia in epidemiologic studies[27], but this association is observed in studies involving multiethnic cohorts, indicating the need for further research is needed to confirm this relationship. Although some scholars have suggested a connection between hearing loss and cognitive impairment, the link between hearing loss and dementia remains unclear.
Alzheimer's disease (AD) is an incurable neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities. It has been found[28]that ARHL is an independent risk factor for Alzheimer's disease, which also causes auditory hypoplasia. It may be biologically related to isolation from social relationships, cognitive burden, deposition of beta-amyloid and Tau proteins, and mitochondrial changes. However, in a Mendelian randomization study[29], it was shown that the clinicopathology of hearing loss and AD is caused by degenerative diseases under the same aging mechanisms and occurs simultaneously. There is no causal genetic relationship between the two, which aligns with the results of the present study. In addition, vascular dementia is the second most common type of dementia after Alzheimer's disease[6, 30]. Hearing impairment as a risk factor is associated with vascular dementia, which may be related to inflammatory responses, oxidative stress in cells, or even the pathogenesis of blood circulation disorders. In contrast, Parkinsonian dementia, with its behavioral symptoms[31–33], mostly neurologically related, is also associated with hearing impairment. The pathogenesis involves the aggregation and diffusion of abnormal proteins (e.g., α-synuclein, tau, or amyloid) in the cortical and subcortical regions. The lack of α-synuclein and efferent neurodegeneration can be both a cause of hearing loss and a potential cause of early-onset Alzheimer's disease. Additionally, studies have shown[34]that hearing loss can lead to mild cognitive impairment, but not necessarily to the extent of dementia. An observational study by Lin FR et al[35]showed that the risk of all-cause dementia increased linearly with the severity of baseline hearing loss. However, in this study, only relevant studies on the association between hearing loss and the risk of dementia up to 2008 were included. Differences in study design, methodology, and the quality of this prospective study make it challenging to establish a causal relationship between ARHL and dementia. In addition, it is worth noting that most of the current studies are observational. Evidence from observational studies should be interpreted with caution because it cannot establish causality and may not fully eliminate the impact of confounding factors.
Our study found that ARHL was associated with dementia (OR = 1.054, 95% CI: 0.633–1.754, P = 0.840). vascular dementia(OR = 1.985, 95% CI: 0.550–7.169, P = 0.295), Parkinson's dementia(OR = 2.263, 95% CI: 0.235–21.774, P = 0.480) and Alzheimer's disease (OR = 1.001, 95% CI: 0.999–1.004, P = 0.392) were positively correlated with an increased risk of dementia, Alzheimer's disease, vascular dementia, and Parkinson's dementia as ARHL increased. This is consistent with the majority of findings that ARHL is positively associated with the risk of developing dementia. However, the results of this study found no causal relationship based on Mendelian inheritance. The higher prevalence of dementia among patients with ARHL compared to the general population can be attributed to the following reasons. First, medication may affect the risk of dementia to some extent in patients with ARHL. Glucocorticoids play a crucial role in the treatment of chronic inflammation. Some patients use glucocorticoids and may experience side effects, which are known to have neurotoxic effects[36–38]. Stress-induced glucocorticoids mediate the induction of brain HMGB1 and down-regulation of CD200R1, which are critical for initiating neuroinflammation. Alternatively, the specific mechanism may be that chronic glucocorticoid use reduces hippocampal volume, a key brain region responsible for learning and memory. Second, both hearing loss and dementia are age-related disorders. While it has been demonstrated that sensorineural hearing loss hinders hippocampal neurogenesis, resulting in cognitive decline, a causal relationship between ARHL and dementia cannot be definitively established due to potential interference from other age-related conditions. Third, ARHL is a common condition among the elderly population who often have multiple comorbidities[39–41]. Approximately 51% of patients have three or more comorbidities, such as hypertension, obesity, dyslipidemia, and depression. The presence of these disorders has been shown to be an independent risk factor for dementia, which may lead to an overestimation of the risk of ARHL with dementia. Fourth, hearing loss can lead to mild cognitive impairment (MCI), but not necessarily to the extent of dementia. The results of this paper show no causal relationship between ARHL and common dementia. To date, several studies have observed significant differences in the pathogenesis, clinical presentation, and genetic susceptibility of patients with ARHL from various ancestral backgrounds. The Genome-Wide Association Study (GWAS) aims to partially explain the intricate genetic structure of ARHL. However, some alleles have not been sequenced in various ancestral backgrounds. Therefore, the possibility remains that important pathogenic genes may be hidden.
Our study has several strengths. First, the primary advantage lies in the MR design, which helps to avoid confounding by confounders and reverse causality. Second, we employed Genome-Wide Association Studies (GWAS) for a thorough screening of SNPs to guarantee the independence of IVs. Third, genetic variation in genomic regions has a larger sample size and is less prone to potentially unmeasurable confounders than traditional observational studies.However, there are several limitations worth mentioning. First, the sample size of this study was relatively small compared to population-based observational studies, although we utilized the largest and most up-to-date GWAS database. Second, epigenetic factors such as DNA methylation, RNA editing, and transposon inactivation are inevitable challenges in MR analysis. Third, since all the populations selected from the GWAS database are of European ancestry, there may be a racial bias in our study. Fourth, detailed demographic and clinical data on the subjects were not available; therefore, subgroup analyses were not performed.