Characterization of the plasma proteomic profile of dual trajectories in cognitive status and physical performance.

Dual declines in cognitive status and physical performance increase dementia risk but shared biological mechanisms between processes remain unclear. We investigated plasma proteomic signatures underlying dual decline in older adults from the Invecchiare in Chianti cohort (n = 774; age ≥ 60). Group-based trajectory models with up to 15 years of data on cognitive status (global Mini-Mental State Examination scores) and 4-m gait speed identified three trajectories that included no decline, physical decline, or dual decline groups. At baseline, 1301 plasma proteins were measured with aptamer-based proteomics (SomaScan). Adjusted multinomial regressions identified proteins associated with group membership. Additional analyses included Reactome functional enrichment and partial least squares discriminant analysis (PLS-DA). Collectively, eight proteins were associated with differences across trajectory groups. Higher PI3, GDF15, TFF3, CCL15, TNNT2, and AGRP were associated with greater odds of dual decline, whereas higher CKM and GHR were linked to lower odds. PLS-DA confirmed and extended these findings. The top discriminators by variable-importance were PTN, TFF3, GDF15, IGFBP-2, and CHRDL1. Hierarchical clustering found PTN, IGFBP-2, PI3, GDF15, and TFF3 formed a coherent module. Functional enrichment highlighted overrepresentation of regulation of IGF transport and uptake by IGF binding proteins across decline trajectories and exploratory enrichment of post-translational protein phosphorylation and diseases of homeostasis. Older adults with dual declines showed a proteomic profile marked by cellular stress, inflammation, barrier injury, reduced IGF-1 bioavailability, and cardiovascular-metabolic strain. These findings support system-level hypotheses of dual decline and warrant replication, longitudinal proteomics, and evaluation of module-level markers.