Association of neurofilament light chain, CXCL9, IL-6, and TNFRSF11B with intrinsic capacity in community-dwelling older adults.

Intrinsic capacity (IC) reflects multidomain functional reserve and a measurable phenotype of healthy ageing, but its biological correlates remain incompletely understood. We examined associations of neurofilament light chain (NfL), CXCL9 and inflammatory biomarkers with IC in community-dwelling older adults. We conducted a cross-sectional analysis within the Screening and Prevention of Intrinsic Capacity Decline in Elders (SPICE) programme. IC was derived from locomotion (SPPB), cognition (MoCA), psychological health (PHQ-9), and vitality (MNA-SF), rescaled to a 0-100 composite and analysed as both z scores and tertiles. NfL, CXCL9, and TNFRSF11B were measured using Olink assays, and interleukin-6 (Il-6) by electrochemiluminescence. Multivariable linear and multinomial regression models assessed associations with IC. Mediation analyses evaluated indirect effects of inflammatory biomarkers via NfL. Among 199 participants (mean age 71.9 ± 5.2 years), NfL, CXCL9, IL-6, and TNFRSF11B increased across decreasing IC tertiles. In multivariate models, only NfL remained independently associated with IC (β - 0.41, 95% CI - 0.72 to - 0.12), with attenuation of other biomarkers after NfL adjustment. Higher NfL was associated with increased likelihood of low versus high IC (RRR 6.62, 95% CI 1.84-23.76). Mediation analyses showed significant indirect effects via NfL for CXCL9 (27.6%) and TNFRSF11B (53.9%), but not IL-6. Domain-specific analyses indicated distinct biomarker associations: NfL with locomotion and psychological health, IL-6 with locomotion, CXCL9 with vitality and TNFRSF11B with cognition. NfL was significantly associated with IC and partially mediated inflammatory associations. Integrating blood-based biomarkers with IC assessment may enhance early detection of multidomain vulnerability in ageing.