Blood-Based Biomarker Predicts Onset of Symptomatic Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, starting with a preclinical phase of normal cognition lasting approximately two decades. The formal diagnosis of AD dementia, relies on neuropsychological tests further confirmed by brain imaging and cerebrospinal fluid (CSF) sampling.

The pathogenic features of AD that have an onset in the preclinical phase may allow identification of such early blood-based biomarkers. By eliciting compensatory responses, these early pathogenic changes were found to initially prevent the increase in reactive oxygen and nitrogen species (ROS/RNS) through activation of antioxidant mechanisms.

Scientists at the University of Brescia (Brescia, Italy) and their colleagues collected blood samples from 482 subjects aged between 60 and 85 years who did not present specific comorbidities (uncontrolled diabetes, vascular disease, severe depression, or psychiatric illnesses) and were included in a retrospective study collecting a total of 515 blood samples from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study by applying a consecutive sampling approach.

The team performed 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 (AlzoSure Predict test, Diadem, Brescia, Italy), representing a measure of the U-p53 conformational variant (U-p53^AZ). Based on U-p53^AZ quantification via IP/LC electrospray ionization-coupled MS/MS (Thermo Scientific EASY-nLC 1000 HPLC system, coupled to a Thermo Fisher Scientific EASYSpray source, Waltham MA, USA), supported by an analytical nanoflow column system. 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.

The investigators reported that 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.

The authors concluded that their 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. The study was published on August 25, 2021 in the journal medRxiv.

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