Inflammatory and genetic mechanisms mediate the association between frailty and incident atopic dermatitis in middle-aged and elderly adults

Frailty is linked to many chronic conditions, but its relationship with atopic dermatitis (AD) remains insufficiently defined. We assessed whether frailty predisposes to incident AD and explored inflammatory and genetic mechanisms. Baseline frailty was ascertained using both the physical frailty phenotype and a multidimensional frailty index, classifying participants as non-frail, pre-frail, or frail. Cox proportional hazards models with stratified analyses quantified associations with AD onset. To probe causality, we performed two-sample Mendelian randomization (TSMR) and generalized summary-data-based MR (GSMR). We further integrated circulating inflammatory markers and plasma proteomic data to illuminate biological pathways. Compared with non-frail participants, pre-frail and frail individuals had higher risks of incident AD after adjustment for established confounders; associations were stronger in adults < 65 years. TSMR and GSMR supported a potential causal effect of frailty on AD. Neutrophil count, eosinophil count, and C-reactive protein partially mediated the frailty-AD relationship. Proteomic analyses highlighted MMP12 as a promising AD-specific biomarker in frail individuals. Overall, frailty confers an elevated long-term risk of AD, with middle-aged adults displaying the greatest vulnerability. Several inflammatory cell measures and circulating proteins-including MMP12-may serve as early indicators of AD risk, informing earlier diagnosis and targeted monitoring in pre-frail and frail populations.