Unveiling the molecular bridge between hearing loss and dementia via plasma proteomic mapping
Feng Chen, Yanggang Hong, Haoxiong Guan, Yue Zhu, Jiajun Li, Xiaobi Fang, Fan YeBackground
Hearing loss (HL) is a potentially modifiable risk factor for dementia, but the circulating molecular features shared by hearing impairment and dementia remain unclear.
Objective
To derive a plasma proteomic signature of hearing impairment and examine its association with incident all-cause dementia and its statistical contribution to the hearing–dementia association.
Methods
We analyzed 13,941 UK Biobank participants with plasma proteomics and speech-in-noise hearing assessments. A proteomic signature of hearing impairment was derived using elastic-net regression with 10-fold cross-validation. A proteomic signature was constructed and tested for associations with incident all-cause dementia using Cox models. Mediation, functional enrichment, and exploratory drug-signature enrichment analyses were also performed.
Results
Elastic-net regression selected 64 proteins, and the composite signature correlated with hearing impairment (point-biserial r = 0.232). Compared with normal hearing, insufficient (HR = 1.338, 95% CI: 1.015–1.763) and poor hearing (HR = 2.021, 95% CI: 1.244–3.283) were associated with higher dementia risk after multivariable adjustment. The proteomic signature was associated with incident dementia (HR = 1.791, 95% CI: 1.312–2.445). Estimated proportions mediated were 22.99% (95% bootstrap CI: 4.87%–129.05%) and 14.61% (95% bootstrap CI: 2.21%–64.21%), respectively. Drug-signature enrichment yielded exploratory compound–protein signals.
Conclusions
In this prospective cohort, hearing impairment and a derived plasma proteomic signature were associated with incident all-cause dementia. These findings provide hypothesis-generating evidence for circulating molecular features shared by hearing impairment and dementia but require external validation and mechanistic investigation before causal or clinical interpretation.