通过血浆蛋白质组图谱揭示听力损失与痴呆之间的分子桥梁

文献信息

中文摘要

背景： 听力损失（HL）是痴呆的一个潜在可改变危险因素，但听力障碍与痴呆所共享的循环分子特征仍不清楚。目的：构建听力障碍的血浆蛋白质组特征，并检验其与 incident 全因痴呆的关联及其对听力-痴呆关联的统计学贡献。方法：我们分析了13,941名具有血浆蛋白质组学和噪声中言语听力评估的英国生物银行参与者。使用弹性网回归结合10折交叉验证构建听力障碍的蛋白质组特征。构建蛋白质组特征并使用Cox模型检验其与 incident 全因痴呆的关联。还进行了中介分析、功能富集和探索性药物特征富集分析。结果：弹性网回归筛选出64种蛋白质，复合特征与听力障碍相关（点二列 r = 0.232）。与正常听力相比，在多变量调整后，听力不足（HR = 1.338，95% CI：1.015-1.763）和听力差（HR = 2.021，95% CI：1.244-3.283）与更高的痴呆风险相关。蛋白质组特征与 incident 痴呆相关（HR = 1.791，95% CI：1.312-2.445）。估计的中介比例分别为22.99%（95% bootstrap CI：4.87%-129.05%）和14.61%（95% bootstrap CI：2.21%-64.21%）。药物特征富集产生了探索性化合物-蛋白质信号。结论：在这项前瞻性队列中，听力障碍和衍生的血浆蛋白质组特征与 incident 全因痴呆相关。这些发现为听力障碍与痴呆共享的循环分子特征提供了产生假设的证据，但在进行因果或临床解释之前需要外部验证和机制研究。

英文摘要

BackgroundHearing loss (HL) is a potentially modifiable risk factor for dementia, but the circulating molecular features shared by hearing impairment and dementia remain unclear.ObjectiveTo 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.MethodsWe 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.ResultsElastic-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.ConclusionsIn 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.