An inflammatory fingerprint in mild cognitively impaired patients is reversed by physical and cognitive training

BACKGROUND: Alzheimer's disease (AD) is a major global health concern, with number of affected individuals expected to rise to 139 million by 2050. Lifestyle factors play a significant role in modulating cognitive decline, and multidomain interventions have demonstrated effectiveness in improving outcomes for populations at risk. The Train the Brain (TTB) program-a combined physical and cognitive training delivered in a social setting-has previously demonstrated cognitive benefits within 7 months. However, the underlying biological mechanisms remain unclear. Given the role of inflammation in aging and neurodegeneration, we investigated whether specific immune biomarkers reflect the efficacy of this intervention. METHODS: We enrolled 76 individuals with Mild Cognitive Impairment (MCI) aged 65-80, into the TTB program. Participants underwent neurological assessment, MRI and blood sampling at baseline and after the intervention. Plasma levels of a comprehensive panel of immune - related biomarkers were measured through Proquantum and ELLA platforms. RESULTS: At baseline, MCI participants displayed elevated levels of IL-17A, CX3CL1, CCL11, with a borderline increase of IL-6 and TNFα. Following the TTB intervention, we observed reductions in IL-6, IL-17A, TNFα, and CCL11 levels. In contrast, anti-inflammatory cytokines (IL-10, TGFβ, IL-4) and BDNF declined in control group but were maintained or increased in the intervention group. CONCLUSION: The TTB intervention not only improved cognitive and physical outcomes but also modulated key immune markers associated with neuroinflammation and aging. IL-10, in particular, emerged as potential peripheral biomarker of training efficacy. These findings support the utility of immune profiling in monitoring response to multidomain interventions and guiding personalized strategies for cognitive risk reduction.