The blood test from Diadem SpA, which quantifies the AZ 284 peptide as readout of U-p53AZ, showed a significantly higher AUC in both time-independent and time-dependent prognostic analyses than gold standard testing.
Newly published findings from a single-center study of the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort suggest that the unfolded conformational variant of p53 (U-p53AZ) biomarker might be able to predict individuals reaching neuropsychologically-defined Alzheimer disease (AD) within 6 years prior to an AD diagnosis.1
The biomarker was identified via the AlzoSure Predict test from Diadem SpA, which includes immunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS), to quantify the AZ 284 peptide as readout of U-p53AZ. This was then compared with an independent neuropsychological diagnosis, while amyloid load, measured via amyloid β-positron PET, and other supporting clinical information were included where possible.
All told, in both time-independent and time-dependent prognostic analyses—conducted at 36, 72, and 90 months post initial sampling—the area under the curve (AUC) was above 98% for U-p53AZ compared with between 84% and 93% for Aß-PET (P <.0001 and P <.001, respectively). Aß-PET is currently the gold standard for the field.
"There is growing interest among physicians and the public for access to tools enabling early identification of individuals likely to develop Alzheimer disease, both to enable those at-risk to seek early interventions, as well as to facilitate the development of effective disease modifying therapies,” study author Colin L. Masters, MD, FAA, AO, professor of dementia research, University of Melbourne, and head, Neuropathology and Neurodegeneration Laboratory, Florey Institute of Neuroscience, said in a statement.2 He added that the AlzoSure Predict “has the potential” to help identify patients years prior to progressing to clinical dementia.
“The fact that it is a simple, potentially cost-effective, and accurate blood test suggests that AlzoSure Predict could play an important role, along with other innovations in AD diagnosis and treatment, in enabling more effective management of this devastating disease," Masters said.2 He and colleagues wrote that integrated U-p53AZ into the screening process could help support more refined participant stratification for interventional studies, as well.
Additionally, as a single factor, U-p53AZ clearly determined the risk of AD neuropsychological diagnosis over time, with am HR of 2.99 for low versus intermediate/high U-p53AZ levels. Proportional hazards regression analysis showed that U-p53AZ levels were a major independent predictor of AD onset.
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The ABIL cohort included 483 participants aged 60 to 85 years without uncontrolled diabetes, vascular disease, severe depression, or psychiatric illnesses—in total, 479 were included in the analysis. At baseline, 270 of the participants were considered non-AD and 209 were considered AD. In the non-AD group, 72 (27%) had no memory complaints, 157 (58%) had some memory complaints, 38 (14%) had mild cognitive impairment (MCI), and 3 (1%) had other dementia at baseline. In the AD group, 141 (68%) had AD at baseline while 60 (29%) had MCI, 2 (1%) had no memory complaints, and 6 (3%) had some memory complaints.
The diagnostic performance was evaluated through two models based on the neuropsychological assessment; the first comparing individuals with AD with those without AD (including those pooled from any other diagnosis than AD), and the second specifically comparing the cognitively normal and MCI subgroups with the AD group.
Masters et al noted that plasma U-p53AZ accurately and reliably refined subjects at the asymptomatic stage (defined as no or some memory complaints) from those with AD (AUC, 99.8%; 95% CI: 99.6-100.0) with a sensitivity of 95.0% and specificity of 99.6%. In differentiating those in the early symptomatic stage (defined as MCI) from those with neuropsychological AD status, the sensitivity and specificity were 95.0% and 91.8%, respectively (AUC, 95.7%; 95% CI: 92.8-98.5%).
“Interestingly, baseline levels of U-p53AZ in individuals with stable neuropsychological MCI through the study [of which there were 38] were significantly lower compared to those MCI patients that developed AD [of which there were 60], suggesting that individuals with MCI who had high U-p53AZ levels at baseline are more likely to convert to neuropsychological AD status over time,” Masters and colleagues wrote, adding that the 8 who changed their neuropsychological classification from cognitively normal to AD showed significantly higher baseline levels of U-p53AZ compared with the 207 who had a stable profile of cognitively normal (Tukey Test, P = .003).1
"Importantly, the test requires only a simple blood draw and widely available laboratory instruments, making it suitable for broad-based public health screening applications,” Paul Kinnon, chief executive officer, Diadem SpA, said in a statement.2 “The potential of AlzoSure Predict was recently recognized by an FDA Breakthrough Device designation and granting of CE-IVD marking, allowing us to begin marketing the test in the EU. We aim to complete additional validation studies in the coming months and are targeting launches in collaboration with strategic partners beginning later this year."
Masters and colleagues noted in the study that these results “confirm and expand” on those from a prior study that utilized a similar technique. Although, they stressed that with their use of a larger study cohort, the predictive performance of U-p53AZ improved. As well, compared with an MRI-, PET-, CSF- and covariates-based model, “the predictive potential of U-p53AZ was higher and without the limitations associated with costs and invasiveness,” they noted.1
Diadem’s AlzoSure Predict has also been granted a breakthrough device designation from the FDA. It is not the only test of its kind, and the statements made by Masters and Kinnon about the “growing interest” in tests of these sort has been echoed by experts in the field. In May 2022, report published by Quest Diagnostics—which has developed its own, the QUEST AD-Detect Amyloid-ß42/40 Ratio test—suggested that 84% of the 501 primary care providers (PCPs) surveyed reported that early AD risk testing result in earlier and improved disease management, and among the more than 2000 individuals of general US population surveyed, 86% believe blood tests for the early detection of AD risk will increasingly become a regular part of preventative care.3
The report did suggest that cost concerns could impede the adoption of such tests, however, as 85% of the PCP cohort noted that these tests’ value depends on reimbursement. Although, 94% of the PCP cohort suggested that blood tests would be more cost effective compared with more invasive methods of detection, such as lumbar punctures or imaging studies.