Functional dependency (FD) is a known risk factor for cardiometabolic multimorbidity (CMM), but underlying biological pathways remain unclear. Circulating plasma biomarkers, including biochemistry, inflammatory, cytokines, and oxidative stress markers, may provide mechanistic insights.

A cross-sectional survey was conducted from February to August 2023 in four Beijing communities. Older adults aged ≥ 60 years who could communicate and consented to participate were recruited. Of 937 initially recruited participants, 533 with complete FD, covariates, and fasting plasma samples were included. FD was assessed by Instrumental Activities of Daily Living (IADL) and Activities of Daily Living (ADL) scales. CMM was defined in two ways: CMM-I, having ≥ 2 of type 2 diabetes, heart disease, or stroke; CMM-II, having ≥ 2 of type 2 diabetes, heart disease, stroke, or visceral obesity. Forty-three plasma biomarkers were measured, and exploratory factor analysis identified latent biological factors. Associations of IADL dependency with biomarker factors and CMM were evaluated using multivariable regression, and mediation was tested via the Karlson–Holm–Breen method.

Five biomarker factors were identified: neuro-inflammation, lipid-immune, lipoprotein/immune complex, neurodegeneration-stress, and adiposity-metabolic. IADL dependency was significantly associated with the Neuro-inflammation factor in fully-adjusted model (β = 3.61; 95%CI: 1.42–5.80). IADL dependency increased the odds of CMM-I (OR = 1.59; 95%CI: 1.06–2.38), with 23.6% mediated by the Neuro-inflammation factor. For CMM-II, 47.8% of the effect was mediated. Key mediators included IL-6, IL-11, and BDNF. Sensitivity analyses confirmed robustness.

Neuroinflammatory and metabolic pathways partially mediate the link between FD and CMM in older adults. Early identification of biomarker risk factors may inform interventions to reduce the dual burden of functional impairment and cardiometabolic multimorbidity.