Featured ArticleAn inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation

•This report revealed plasma proteome alterations in proNGF, metallo-proteases, inflammatory mediators, and amyloid peptides in a cohort of Down syndrome individuals examined longitudinally•Baseline levels of plasma Aβ40 and Aβ42 correlated with prospective cognitive decline•A significant association was also found between cognitive decline and the longitudinal decrease in plasma Aβ42 along with a rise in proNGF•A combined measure of Aβ and inflammatory molecules was a strong predictor of prospective cognitive deterioration in Down syndrome•The plasma changes in NGF-related markers and inflammatory mediators could offer a novel paradigm to identify Down syndrome individuals likely to convert to Alzheimer's disease•The above findings might be of significance for the study of silent stages of the Alzheimer's pathology in the general population

IntroductionGiven that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need.MethodsWe investigated the plasma levels of Aβ, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline.ResultsAβ40 and Aβ42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aβ correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aβ42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aβ and inflammatory molecules was a strong predictor of prospective cognitive deterioration.ConclusionsOur findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.