Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Performance of a Non-Invasive Blood Test for a Conformational Variant of p53 to Predict Alzheimer’s Disease Within 6 Years of Clinical Diagnosis

Version 1 : Received: 11 May 2021 / Approved: 12 May 2021 / Online: 12 May 2021 (11:21:18 CEST)

How to cite: Piccirella, S.; Uberti, D.; Xiong, C.; Fowler, C.; Doecke, J.; Fagan, A.; Frisoni, G.; Kinnon, P. Performance of a Non-Invasive Blood Test for a Conformational Variant of p53 to Predict Alzheimer’s Disease Within 6 Years of Clinical Diagnosis. Preprints 2021, 2021050267 (doi: 10.20944/preprints202105.0267.v1). Piccirella, S.; Uberti, D.; Xiong, C.; Fowler, C.; Doecke, J.; Fagan, A.; Frisoni, G.; Kinnon, P. Performance of a Non-Invasive Blood Test for a Conformational Variant of p53 to Predict Alzheimer’s Disease Within 6 Years of Clinical Diagnosis. Preprints 2021, 2021050267 (doi: 10.20944/preprints202105.0267.v1).

Abstract

Background: Research continues to search for blood-based biomarkers sensitive to Alzheimer’s disease (AD) pathology during the initial stages when symptoms of cognitive decline are not yet apparent. A blood-based biomarker candidate is metalloprotein p53, the conformation of which was previously found to be altered in peripheral cells from individuals with mild cognitive impairment (MCI) and AD, presenting as an unfolded p53 (U-p53) conformational variant. Methods: Plasma samples from the well-characterized Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort were used to identify the clinically relevant AZ 284® peptide, specifically present in samples from individuals with symptomatic AD. The AZ 284® peptide, which is a marker of the U-p53 conformational variant (U-p53AZ), was identified by immunoprecipitation (IP) with a novel U-p53 conformational variant-specific antibody followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing. Using IP-LC surface-activated chemical ionization (SACI) MS/MS analysis, the prognostic and diagnostic performance of U-p53AZ were examined in the longitudinal AIBL cohort, including 252 plasma samples derived from 214 elderly individuals. For the prognostic analyses, U-p53AZ levels were assessed at 36, 72, and 90 months after baseline assessment. Results: The prognostic performance of U-p53AZ to predict the progression to AD from preclinical or prodromal AD was high, with area under the receiver operating characteristic curve (AUC) values close to or above 0.90. Furthermore, U-p53AZ predicted the progression to AD more than 6 years prior to symptom onset with positive and negative predictive values of about 90%. Additionally, the estimated prognostic performance of U-p53AZ was superior to other main risk factors (i.e., age, sex, and either alone or in combination with amyloid status. Furthermore, U-p53AZ had high diagnostic performance to differentiate cognitively normal individuals from those with AD (AUC values >0.88). Conclusion: These findings support the use of U-p53AZ as a prognostic blood-based biomarker accurately predicting the progression to AD dementia during the preclinical and prodromal stages at least 6 years before receiving the clinical diagnosis of AD dementia.

Keywords

Alzheimer’s disease; AD; blood-based biomarker; p53; unfolded p53; U-p53

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