Liver fibrosis, plasma proteins, and incident dementia: Unraveling proteomic biomarkers of the liver–brain connection in UK Biobank cohort
Zhichong Guan, Fangfei Li, Jiayi Mai, Hangqian Zhang, Wanmin Liang, Xiaojing Meng, Fei Zou, Zongji Zheng, Yao Liu, Bin WangBackground
Although liver fibrosis has been linked to dementia, including Alzheimer's disease, the underlying molecular mechanisms remain unclear.
Objective
To determine whether the fibrosis-4 (FIB-4) index modifies associations between plasma proteins and incident all-cause dementia and assess the biological and prognostic relevance of identified interactions.
Methods
In this prospective UK Biobank study, 2923 plasma proteins were measured using the Olink Explore platform in 48,754 dementia-free participants. Cox proportional hazards models tested protein–FIB-4 interactions for incident all-cause dementia. Robust interaction signals were evaluated across FIB-4 strata and in age-focused sensitivity analyses and analyses restricted to original non-imputed protein measurements. In participants with high FIB-4, candidate proteins were prioritized by exploratory machine learning and evaluated for incremental prognostic value using internally validated ridge-penalized Cox regression. Functional enrichment characterized interacting proteins.
Results
Nine proteins showed robust interactions with FIB-4, including TNR (interaction HR = 1.57, 95% CI 1.23–2.01) and CD207 (interaction HR = 1.41, 95% CI 1.14–1.73). Based on protein annotations and enrichment results, these interaction signals were primarily related to inflammatory and immune processes, vesicular transport, and extracellular matrix organization. In predictive analyses within the high FIB-4 subgroup, TNR and CD207 provided the greatest incremental value; adding these proteins to the clinical reference model increased the optimism-corrected C-index from 0.732 to 0.764.
Conclusions
FIB-4 identifies heterogeneity in dementia-associated plasma protein profiles. Functional and pathway enrichment analyses of the interacting proteins suggest a potential “liver–brain connection,” and CD207 and TNR may serve as candidate biomarkers for risk stratification in individuals with high FIB-4.