Alzheimer’s disease is a devastating neurodegenerative disease, affecting nearly 44 millions of elderly worldwide. Early diagnosis is a crucial starting step in the management of the disease, allowing early interventions in the high-risk individuals before cognitive symptoms are over-claimed, and brain irreversible damaged. In fact, it is now well established that clinical manifestation of AD is preceded by a long prodromal stage, during which pathophysiological processes occur in the brain and peripheral tissues. Our research focused on the characterization of redox alterations as a signature of AD pathophysiology. In particular, the activity of antioxidant enzymes and the expression of post‑translational redox‑modified products were evaluated in blood samples of two independent studies. Initially, 10 variables related to redox steady state in a total of 88 blood samples from individuals with presymptomatic to large state Alzheimer’s disease and healthy subjects (HS) were analyzed. Using visualizing data and machine learning methods we identified a peculiar blood‑based redox profile characteristic of the disease. Through the clustering and random forest analysis, nitrated p53 isoform was identified as the variable that impacts more on AD classification, and cross‑validated on an independent cohort derived from a retrospective longitudinal based population study “InveCe.Ab”. Among approximately 1000 individuals of 75–79 years old, resident in Abbiategrasso, Italy, we processed, at different time points (baseline, 2 and 4 years later), plasma samples from 46 HS, and 27 MCI patients, some of which, included HS, converted in AD. The lead biomarker was validated using regression tree method that assessed the classification of unknown samples, carrying out a prediction of AD (sensitivity 86% and specificity 95%). Our data indicate that a highly specific biomarker related to blood based redox profile can characterize AD years before a clinical diagnosis can be made. FINANCIAL SUPPORT: This study was supported by the Italian Ministry of Instruction, Research and University (MIUR) (grants to D.Uberti 2008R25HBW_004; PAN LAB PON A3_00166 and 2009B7ASKP_006 both to M. Memo), a grant from Regione Lombardia ‘Network Enable Drug Design’ (NEDD) the Spanish Ministry of Science and Technology (grants CTQ2008‑06754‑C04‑03/PPO and SAF2011-28883-C03-03 both to A.Novelli), and DIADEM Ltd, Spin Off of University of Brescia.
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