Frailty and the Incidence of Major Ocular Diseases: A Prospective Cohort Study Integrating Proteomic Mediation Analysis

<title>Abstract</title> <p> Background The long-term association between frailty phenotype and major vision-threatening ocular diseases (age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, and cataract), as well as the underlying molecular mechanisms, remain unclear. Methods Cox proportional hazards models were used to assess the association between frailty status (classified as non-frail, prefrail, or frail) and the risk of four ocular diseases. Olink proteomics identified plasma proteins signatures associated with frailty status and ocular diseases. Mediation analysis assessed the overall and stage-specific (prefrail vs. frail) proteins as potential mediators. Results During a median follow-up of 15.7 years, prefrailty and frailty were associated with significantly elevated risks of AMD (Prefrail: HR = 1.17; Frail: HR = 1.49), DR (Prefrail: HR = 1.96; Frail: HR = 3.91), glaucoma (Prefrail: HR = 1.13; Frail: HR = 1.61), and cataract (Prefrail: HR = 1.16; Frail: HR = 1.49) (all <italic>P</italic>  &lt; 0.001). Proteomic profiling revealed 1,068 and 1,387 proteins associated with prefrailty and frailty, respectively, enriched in immune-inflammatory pathways (e.g., leukocyte migration). Similarly, proteins associated with all four ocular diseases were enriched in inflammatory and cell adhesion pathways. Mediation analysis further demonstrated that a spectrum of plasma proteins partially explained these associations, with a stage-specific escalation in the proportion of harmful mediators observed in DR. Conclusions These findings establish a significant link between frailty and common ocular diseases, unveiling a mediating role of systemic inflammatory and extracellular matrix proteins, with a progressive, stage-specific pattern in DR. These results highlight frailty as both a marker of shared pathways in systemic and ocular aging, and a potential integrated biomarker for interventions aimed at preventing vision loss. </p>