Searching for New Possible Peripheral Biomarkers of Cognitive Decline in Down Syndrome: The Role of IL-18 Pathway and its Interaction with TGF-β1 and TNF-α

Down syndrome (DS) represents one of the most common genetic disorders attributable to a partial or complete trisomy of chromosome 21 that affects about 1 in 700 individuals at birth. The diagnosis of Alzheimer's Disease (AD)-correlated cognitive decline in this population requires new approaches and new biomarkers that comprehensively assess health status and early cognitive decline. In this observational study, we explored for the first time the relation of IL-18, a cytokine member of IL-1 family involved in both innate and acquired immune responses, with DS associated cognitive decline. We observed that plasma total IL-18, in subjects with DS over 35 with and without AD-related cognitive decline, and plasma concentrations of its binding protein in subjects with DS (19-35 years) were correlated with lower plasma concentrations of Transforming Growth Factor (TGF-beta 1), which are linked to an increased rate of cognitive decline in adults with DS. In addition, we found a significant association between low baseline concentrations of Free IL-18, the active form of the cytokine, and an increased rate of cognitive decline at 12 months, calculated as delta of the Test for Severe Impairment (dTSI), in individuals with DS (19-35 years). Finally, we demonstrated a reduction of Free IL-18/TNF-alpha ratio, considered as a new possible double biomarker, in both young and older adult DS subjects without AD-related cognitive decline (area under the receiver operating curve (AUC) was 0.82 and 0.71, respectively), suggesting the advantage of the composite biomarkers in the discrimination of patients from healthy people over single biomarkers.