A conformational variant of p53 (U-p53 AZ ) as blood-based biomarker for the prediction of the onset of symptomatic Alzheimer’s disease

Abstract Background Ongoing research seeks to identify blood-based biomarkers able to predict the onset and progression of Alzheimer’s disease (AD). A potential biomarker is the unfolded conformational variant of p53, previously observed in individuals in the prodromal and clinical AD stages. In this retrospective study, we compare diagnostic and prognostic performances of measures of the amyloid β load with those of a conformational variant of U-p53 in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort. Methods Immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing in plasma samples from the AIBL study identified the clinically relevant AZ 284 ® peptide, representing a measure of the U-p53 conformational variant (U-p53 AZ ). Based on U-p53 AZ quantification via IP/LC electrospray ionisation-coupled MS/MS (AlzoSure ® Predict test) on 515 samples from 482 individuals from the AIBL cohort, the predictive performance of U-p53 AZ was assessed and compared with amyloid load as measured by amyloid β-positron emission tomography (Aβ-PET). Its predictive performance was determined at 36, 54, 72 and 90 months following baseline assessment. Results U-p53 AZ was able to identify individuals with AD dementia with an area under the receiver operating characteristic curve (AUC) of 99%. U-p53 AZ outperformed the conventional Aβ-PET measures in predicting the onset of AD dementia both from preclinical (AUC=98%) and prodromal stages (AUC=89%), even 90 months prior to onset (AUC=99%). Additionally, the estimated predictive performance of U-p53 AZ was superior (AUC ≥98%) to other risk factors (i.e., gender, Aβ-PET and APOE ε4 allele status) in identifying individuals at high risk for progression to AD. Conclusion These findings support use of U-p53 AZ as blood-based biomarker predicting if individuals, at both asymptomatic and MCI stages, would progress to AD at least six years prior to the onset of clinical AD dementia.