A Conformational Variant of p53 (U-p53^AZ) as Blood-Based Biomarker for the Prediction of the Onset of Symptomatic Alzheimer’s Disease

Background: Ongoing research seeks to identify blood-based biomarkers able to predict onset and progression of Alzheimer’s disease (AD). Objective: The unfolded conformational variant of p53 (U-p53^AZ), previously observed in AD individuals, was evaluated in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort for diagnostic and prognostic assessment, validated on a neuropsychological-based diagnosis, over the course of six years. Design: Retrospective Longitudinal Prognostic biomarker study. Setting: Single-center study based on the AIBL cohort. Participants: 482 participants of the AIBL cohort, aged 60–85 years, without uncontrolled diabetes, vascular disease, severe depression or psychiatric illnesses. Measurements: The AlzoSure® Predict test, consisting of immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS), was performed to quantify the AZ 284® peptide as readout of U-p53^AZ and compared with an independent neuropsychological diagnosis. The amyloid load via amyloid β-positron emission tomography (Aβ-PET) and supporting clinical information were included where possible. Results: U-p53^AZ diagnostic and prognostic performance was assessed in both time-independent and time-dependent (36, 72 and 90 months following initial sampling) analyses. Prognostic performance of Aβ-PET and survival analyses with different risk factors (gender, Aβ-PET and APOE ε4 allele status) were also performed. U-p53^AZ differentiated neuropsychologically graded AD from non-AD samples, and its detection at intermediate/high levels precisely identified present and future symptomatic AD. In both time-independent and time-dependent prognostic analyses U-p53^AZ achieved area under the curve (AUC) >98%, significantly higher than Aβ-PET AUCs (between 84% and 93%, P respectively <0.0001 and <0.001). As single factor, U-p53^AZ could clearly determine the risk of AD neuropsychological diagnosis over time (low versus intermediate/high U-p53^AZ hazard ratio=2.99). Proportional hazards regression analysis identified U-p53^AZ levels as a major independent predictor of AD onset. Conclusions: These findings support use of U-p53^AZ as blood-based biomarker predicting whether individuals would reach neuropsychologically-defined AD within six years prior to AD diagnosis. Integration of U-p53^AZ in screening processes could support refined participant stratification for interventional studies.