Exploring the Vestibular–Cognitive Axis: A Case–Control Study of BACE1 rs638405 and Cognitive Vulnerability in Vestibular Dysfunction

Abstract

Background:
Alzheimer’s disease (AD) is a leading cause of cognitive decline worldwide and involves complex interactions between genetic, neurodegenerative, and environmental factors [1–3]. Increasing evidence suggests that vestibular dysfunction contributes to cognitive impairment through disruption of hippocampal-dependent processes [17–20]. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a central role in amyloid-β metabolism and synaptic regulation [8,13]; however, the role of BACE1 genetic variation in vestibular-related cognitive vulnerability remains insufficiently explored.

Objective:
To investigate the association between the BACE1 rs638405 polymorphism and vestibular dysfunction, and to evaluate patterns of cognitive impairment across study groups.

Methods:
This exploratory case–control study included 108 participants aged 25–80 years: vestibular system dysfunction (VSD) (n = 45), Alzheimer’s disease (AD) (n = 21), and healthy controls (n = 42). Cognitive performance was assessed using standardized neuropsychological instruments [29–31]. Genotyping of the rs638405 polymorphism was performed using TaqMan real-time PCR assays. Genotype distributions were compared using Fisher’s exact test, and crude odds ratios (OR) with 95% confidence intervals (CI) were estimated using logistic regression.

Results:
The GG genotype of rs638405 was more frequent in the VSD group compared with controls (24.4% vs 7.1%; p = 0.045; OR = 4.51; 95% CI: 1.04–19.66). This marginal statistical significance should be interpreted with caution given the limited sample size and absence of multiple-testing correction. No statistically significant association was observed between rs638405 and AD. Cognitive impairment was identified in 64% of patients with vestibular dysfunction.

Conclusion:
These findings suggest a preliminary genetic signal linking BACE1 variation to cognitive vulnerability in vestibular dysfunction, supporting the concept of a vestibular–cognitive axis. However, given the modest sample size, borderline statistical significance, and lack of adjustment for multiple comparisons, the results should be interpreted as exploratory and require confirmation in larger, multi-center studies with comprehensive genetic profiling and adjusted analyses.

Keywords:
BACE1; rs638405; vestibular dysfunction; cognitive impairment; Alzheimer’s disease; genetic polymorphism