Diadem Announces Publication of Peer-Reviewed Article Describing How Post-Translational Modifications of p53 Variants May Contribute to Development of Alzheimer’s Disease
—Includes Multiple Studies Demonstrating that Post-Translational Modifications of Conformational Variants of p53 Are Associated with the Pathogenesis of Alzheimer’s Disease—
Study author Rakez Kayed, PhD, Professor and John Sealy Chair for Parkinson's Research at the Mitchell Center for Neurodegenerative Disorders of the University of Texas Medical Branch at Galveston, commented, “Increasing evidence suggests that certain conformational variants and post-translational modifications of the p53 protein may contribute to the development of Alzheimer’s disease. This review aims to summarize what researchers have uncovered to date about the transformation of p53 into variants and PTMs that impact amyloid, tau and other pathways implicated in the neurodegenerative processes that ultimately result in symptomatic AD. This knowledge is contributing to our growing understanding of the pathophysiology of AD, as well as the development of novel prognostic and diagnostic biomarker tests that could enable use of more effective therapeutic interventions earlier in the disease process.”
In the new publication, the authors note that the p53 protein, known as “the guardian of the genome” for its role in cancer, plays diverse roles in maintaining cellular function, and that changes in the protein’s functional activity can affect its downstream impact. The p53 protein has more recently gained attention for its possible role in the early evolution of Alzheimer’s disease, partly through its involvement in the regulation of oxidative stress, which is a critical factor in AD initiation and progression. Oxidative stress also has a strong relationship to amyloid β and tau-induced neurotoxicity, fueling feedback loops that may accelerate disease progression.
A key focus of the review is p53 post-translational modifications, which are seen as the most widespread and effective cellular mechanisms controlling p53 function. PTMs affect the conformation of p53, increasing its ability to adopt multiple structural and functional states. A number of these are implicated in the development of AD, including functional dysregulation and loss of function in cellular response pathways. The authors also cite multiple studies showing that the conformational unfolding of p53 impacts its role, directly increasing or decreasing the activation of specific AD-associated pathways. They conclude that there is significant evidence supporting the potential role of p53 PTMs in Alzheimer’s pathogenesis, and recommend additional studies to further elucidate PTM mechanisms and their involvement in the development of AD.
Paul Kinnon, CEO of Diadem, noted, “Our AlzoSure blood-based test for the early prediction of AD is based on decades of research on the role of p53 and its conformational variants in the development of Alzheimer’s disease. This new publication adds to the growing evidence that the loss of p53 function via post translational modifications to the linear sequence of the protein can result in upstream and downstream effects on amyloid and tau metabolism, as well as on other pathways involved in AD pathogenesis. It is consistent with the results of our clinical studies showing that AlzoSure® Predict can identify whether individuals will or will not progress to Alzheimer’s dementia years before the disease is fully symptomatic.”
AlzoSure® Predict is a non-invasive biomarker blood test that can identify with high accuracy whether individuals over the age of 50 with signs of cognitive impairment will or will not progress to Alzheimer’s disease up to six years before definitive symptoms are apparent. Its utility is supported by clinical data from a large longitudinal study that was the basis for AlzoSure® Predict’s recent CE-IVD marking, which allows the test to be marketed in the E.U., as well as for a Breakthrough Device designation from the U.S. Food & Drug Administration. The company’s technology uses an analytical method that includes a patented antibody developed by Diadem and designed to bind to U-p53AZ and its target sequences. U-p53AZ is a conformational variant of the p53 protein that has been implicated in the pathogenesis of AD in multiple studies.
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 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 prognostic and diagnostic methods.
Diadem was founded as a spin-out 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 and cost-effective 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 longitudinal clinical studies that were the basis for awarding CE-IVD marking in the EU and a Breakthrough Device designation in the US. Additional retrospective and prospective clinical trials are ongoing to further validate clinical claims and support widespread adoption and use. Diadem is also developing AlzoSure® Confirm, a blood-based diagnostic test for AD that has shown promising results in early studies. 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 commercialization of AlzoSure® Predict in collaboration with global strategic partners. For more information, visit www.diademdx.com/.