New Scientific Publications Show Diadem's Blood-Based AlzoSure® Biomarker Test Can Predict Which Patients Will Progress to Alzheimer's Disease Years Before Symptoms Occur

MILAN, Italy, Feb. 1, 2021 /PRNewswire/ -- Diadem srl, a company developing the first blood-based test for the early prediction of Alzheimer's disease (AD), today announced the publication of three new scientific studies that support the utility of its biomarker assay to identify individuals at high risk for AD. The publications describe the role of a conformational variant of the p53 protein ( U-p53^AZ) in the pathogenesis of AD, as well as its applicability as a predictive biomarker to identify individuals likely to progress to AD up to six years before symptoms appear. Two of the papers report the results of early studies that confirm the accuracy of the U-p53^AZ-based assay, in development by Diadem as AlzoSure^® Predict, as a prognostic test for AD.

Diadem is developing the AlzoSure assay as a simple, non-invasive plasma-based biomarker test to accurately predict the probability that a patient with asymptomatic mild cognitive impairment (MCI) will progress to Alzheimer's dementia. The company's patented technology uses an analytical method that includes a proprietary antibody designed to bind to U-p53^AZ and target sequences developed by Diadem. Further clinical studies of the assay are underway, and the company plans a global launch in collaboration with strategic partners later this year.

"Together, these studies highlight why we are so excited about the potential of AlzoSure to have a major impact on this devastating disease," said Paul Kinnon, CEO of Diadem. "They describe how this conformational variant of p53 contributes to the ongoing pathology of AD, as well as how its role in disease progression makes it useful as a biomarker to identify patients whose neurons are already under attack. The simplicity and affordability of our blood-based biomarker test mean that it will be available to individuals in primary care settings, which will make widespread screening feasible. This is turn will help spur the development of new drugs for AD, which now will be able to be widely administered early in the disease process, when the chances for slowing and stopping the cognitive ravages of AD are the greatest."

The first publication¹, The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer's disease, was published in Alzheimer's Research & Therapy. It reviews the role of the p53 protein in the development of Alzheimer's disease. As "the guardian of the genome", p53 is most associated with tumor suppression. However, growing evidence shows that dysregulated p53 activity may also contribute to changes in the brain and peripheral nervous system during the early stages of AD. The review describes how p53 dysregulation may exacerbate AD pathology by interfering with a variety of key defense mechanisms that protect neurons and prevent their degeneration. These mechanisms include regulation of inflammation, control of synaptic function, maintenance of redox homeostasis, reduction of amyloid β peptides and inhibition of neuronal cell cycle re-entry. 

The authors describe the possible causes of this p53 conformational change and its impact on neuronal function. The conformational variant of p53 has been found in peripheral neuronal cells in patients with mild cognitive impairment (MCI) and with AD. As has been previously described in the scientific literature, levels of unfolded p53 are significantly higher in peripheral cells derived from patients with AD compared with non-demented controls and are also significantly higher than in patients with Parkinson's disease and other types of dementia. Researchers also expect that unfolded p53 is present in the brain of dementia patients, but this has yet to be confirmed. Because unfolded p53 appears early in the disease process and helps fuel the increasing pathology seen over time in AD, the authors conclude that it has potential to serve as a biomarker for the early detection of AD. 

The second article², A conformation variant of p53 combined with machine learning identifies Alzheimer disease in preclinical and prodromal stages, was recently published in the Journal of Personalized Medicine. It reports on a study from the University of Brescia assessing Diadem's blood-based prognostic test for AD. The assay measures the conformational variant of p53 (U-p53^AZ) as a biomarker to identify individuals at high risk for the early onset of the condition, using a patented monoclonal antibody specifically developed for this purpose by Diadem researchers.

In their introduction, the researchers point out that while U-p53^AZ (referred to in this study as U-p53 ^2D3A8+) is a relatively unknown player in AD, it has demonstrated the features needed for a credible biomarker of biological processes involved in the development of AD. In their prior work, they had identified the increased expression of unfolded p53 in fibroblast and blood cells derived from both AD patients and MCI patients who converted to AD, as well as in AD and MCI plasma specimens. The fact that U-p53^AZ is highly expressed in both the preclinical and early symptomatic stages of AD make it a good candidate as a prognostic biomarker.

In this study, the researchers confirmed that the Diadem-developed and patented antibody is a reliable tool for recognizing the U-p53^AZ conformational variant. The approach was tested in a longitudinal study of 375 subjects in well-characterized cohorts. U-p53^AZ plasma levels correlated with the clinical evolution of the disease, as described by longitudinal analysis, and showed high accuracy in discriminating individuals who converted to AD versus non-converters. The assay achieved an overall 86.7% agreement with clinical diagnosis. Importantly, the algorithms used in the assay also accurately classified MCI patients who will develop AD (AUC = 0.92) . These subjects were stratified using recognized AD markers from cerebral spinal fluid. A machine learning approach to predict AD risk was also developed that combined measurements of U-p53^AZ plasma levels with a standardized test for cognitive impairment and levels of apolipoprotein E-4 (a protein subtype that is implicated in AD).

The researchers note that the Alzheimer's Precision Medicine Initiative (APMI) working group recommends that a blood-based AD biomarker should provide a tool in the primary care setting to assess subjects who are subjectively cognitively normal or have very early signs of cognitive decline, allowing identification of the at-risk subset who require further evaluation and early intervention. The study authors conclude that the biomarker test based on measurements of plasma levels of U-p53^AZ represents a promising blood-based biomarker for AD that could meet the urgent need identified by the APMI.

The third publication, Discovery of simple blood based test to predict early onset of Alzheimer's using standard clinical mass spectrometry platforms, has just been released as a preprint and is also being submitted to a peer-reviewed journal for publication. It reports on another early longitudinal study of Diadem's AlzoSure prognostic assay. The authors begin by noting that despite the increasing number of individuals affected by AD every year, no effective therapy has yet been approved. A major factor underlying the lack of disease-modifying therapeutics is the inadequacies of current diagnostic methods, which only identify AD years after molecular damage to the central nervous system has been underway. Earlier diagnosis would make it feasible to initiate disease-modifying therapies much earlier in the disease process.

Knowing that the p53 conformational variant (U-p53^AZ) had been correlated with AD, the researchers developed a mass spectrometry method for precise quantification of the p53 conformational variant from plasma. They analyzed 107 plasma samples from patients with known clinical outcomes at different time points and tested the prognostic performance of the AD-specific U-p53^AZ peptide (AZ 284) in different sets of individuals, progressing from cognitive normal or mild cognitive impairment to AD dementia. Brain amyloid burden by PET imaging data was available for most of the plasma samples and apolipoprotein E-4 levels were also measured. Participants were classified as cognitively unimpaired (CU), as MCI, or as presenting symptomatic AD. For each diagnostic group, changes of status at the follow-up visits (after 18 and 36 months) were reported.

Using this well-characterized longitudinal cohort, the researchers demonstrated that U-p53^AZ successfully predicted MCI progression to AD at least 36 months earlier, and in a cognitively unimpaired subject, it did so at least six years before symptoms became apparent. Diagnostic performance of the U-p53^AZ peptide in the individuals progressing from cognitive normal and mild cognitive impairment to AD dementia confirmed that quantitative analysis of U-p53^AZ is a reliable tool for prediction of AD progression up six years in advance of diagnosis, with AUC≥ 90%. The authors conclude that taken together, the results support the implementation of the U-p53^AZ biomarker as an affordable and powerful prognostic tool for the early, non-invasive diagnosis of AD in individuals with no symptoms or with early symptoms of cognitive impairment.

The study authors also note that availability of this type of accurate, non-invasive, inexpensive test could enable clinical trials for new AD therapies much earlier in the course of the disease when interventions are more likely to be effective. They also point out that it would be helpful to confirm these findings in a larger study. Diadem is currently conducting further validation studies in about 1000 subjects. 

About Alzheimer's Disease
There are about 50 million people suffering from dementia worldwide. Alzheimer's disease is the most common form and accounts for 60-70% of cases. At present there are no disease modifying treatments for Alzheimer's, and therapies to treat symptoms are limited. There are about 10 million new cases per year, and the incidence is rising rapidly as the population ages. The current total cost of care is enormous--estimated at 1 trillion dollars in the U.S. annually and expected to double by 2030. Currently, diagnosis of Alzheimer's disease is slow, inconclusive, invasive and expensive. Development of effective therapies for Alzheimer's  has been hindered by the lack of accurate and cost-effective diagnostic and prognostic methods.

1 - Abate, G., Frisoni, G.B., Bourdon, JC. et al. The pleiotropic role of p53 in functional/dysfunctional neurons: focus on pathogenesis and diagnosis of Alzheimer's disease. Alz Res Therapy 12, 160 (2020). https://doi.org/10.1186/s13195-020-00732-0  

2 - Abate, G.; Vezzoli, M.; Polito, L.; Guaita, A.; Albani, D.; Marizzoni, M.; Garrafa, E.; Marengoni, A.; Forloni, G.; Frisoni, G.B.; et al. A Conformation Variant of p53 Combined with Machine Learning Identifies Alzheimer Disease in Preclinical and Prodromal Stages. J. Pers. Med. 2021, 11, 14. https://dx.doi.org/10.3390/jpm11010014

3 - Piccirella, S.; Cristoni, S.; Fowler, C.; Doecke, J.; Abate, G.; Uberti, D. Discovery of Simple Blood-Based Test to Predict Early Onset of Alzheimer's Using Standard Clinical Mass Spectrometry Platforms. Preprints 2021, 2021010530 https://doi:10.20944/preprints202101.0530.v1

About Diadem
Diadem was founded as a spin-off of the University of Brescia (Italy). The company is developing the first blood-based prognostic test for the early detection of dementia, with a focus on Alzheimer's disease. The lack of accurate, accessible and affordable diagnostic tools is a major contributor to the absence of effective treatments for this devastating condition. As a result, patients are not diagnosed until late in the illness, when effective treatment is no longer possible. Diadem's rapid, accurate, cost effective and predictive blood-based prognostic test makes it possible for the first time to identify patients early in the disease process, when effective interventions and better outcomes are far more feasible. The utility of the approach has been demonstrated in early clinical studies. Additional retrospective and prospective clinical trials are planned to further validate clinical claims and support widespread adoption and use. Diadem's founding lead investor is Milan-based Panakes Partners, a venture capital firm that finances promising high potential biomedical companies in Europe and Israel. Diadem is preparing for rapid commercialization of its initial Alzheimer's prognostic via a global launch in collaboration with strategic partners, targeted for 2021. For more information, visit www.diademdx.com/.

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