Diadem SpA, a company developing the first blood-based test for the early prediction of progression to Alzheimer's disease (AD), announced the release of a new peer-reviewed publication, Post-Translational Modifications of the p53 Protein and the Impact in Alzheimer's Disease: A Review of the Literature, in the current issue of the journal Frontiers in Aging Neuroscience. The article reviews the extensive scientific literature that elucidates how post-translational modifications (PTMs) of the protein are associated with the development of Alzheimer's disease. Diadem is leveraging the relationship between p53 conformational variants and AD to develop blood-based prognostic and diagnostic assays for Alzheimer's disease. Its most advanced product, the AlzoSure Predict assay, is a simple, non-invasive plasma-based biomarker test to accurately predict whether or not a patient with asymptomatic mild cognitive impairment will progress to Alzheimer's dementia up to six years before the disease fully manifests.

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."