Renew Biotechnologies’ subsidiary Resonant recently published research in the journal Frontiers in Neurology of a new blood biomarker that promises earlier diagnosis of Alzheimer’s disease (AD). The approach, which centers on the use of cell-free DNA (cfDNA) analyzes differential methylation regions (DMRs) to identify biomarkers that can distinguish neuron-derived cfDNA from non-neuron derived cfDNA.
According to the Resonant researchers, the biomarker achieved 100% accuracy in identifying patients with Alzheimer’s disease and—crucially—also identified people with mild cognitive impairment (MCI), the clinical precursor to AD, who developed the disease within five years. The non-invasive, blood-based approach, if further developed, has the potential to significantly impact the diagnosis, monitoring, and treatment of AD.
“Our research suggests that analyzing a simple blood draw can predict whether individuals with MCI will develop Alzheimer’s disease within five years,” said Timothy Jenkins, PhD, co-founder of Resonant. “These data demonstrate significant potential for this technology’s use as a clinically actionable predictor of neurodegeneration, which could allow for pre-symptomatic interventions. We believe that such early identification is the key to improving outcomes for patients with neurodegenerative disease.”
The Resonant team note that finding assays to detect neuron death which characterizes AD and associated biomarkers has been limited to date by the tests’ lack of specificity. The company’s assay, however, differs from previous approaches as it is able to distinguish and analyze neuron-type specific DNA found in a routine blood draw. This method allows for biological detection of the disease, which today is typically diagnosed by a patient’s cognitive symptoms and by the presence of amyloid proteins. But as Resonant co-founder Chad Pollard noted: “by the time these symptoms appear, the disease has progressed too far to significantly alter its trajectory. We are determined to change this.”
For their research, the team first identified 37,455 DMRs between purified cortical neurons and blood plasma samples, which indicated a substantial phenotypic difference. The group further narrowed down to 957 sites with significant mean methylation difference and from this group, the investigators selected 25 target sites as potential biomarkers. The study authors noted that there is a limitation of focusing on the limited set of loci and the need to develop a more comprehensive model incorporating more loci to enhance diagnostic accuracy.
The team also noted technical variance associated with PCR amplification and bisulfite conversion as other potential challenges that could affect the consistency of results. The team suggested that nanopore sequencing could be a better platform for performing these tests.
Yet despite these shortcomings, the new research highlights the potential of using cfDNA analysis as a method of pre-symptomatic detection as well as monitoring not just AD, but other neurodegenerative diseases as well. Using the conservative cutoff of 5% for neuron-derived cfDNA, the researchers demonstrated an ability to accurately identify patients with AD. Further, the ability to stratify patient with MCI who later progressed to AD and those who did not shows the high potential for this approach to be a powerful tool for early detection and prognostic assessment.
Resonant is currently working to increase the assay’s cell-specificity and predictive power in individuals with MCI, working with its laboratory services partner Wasatch Bio Labs, using the company’s proprietary DNA sequencing technology.
The company is also exploring the use of its technology beyond AD to include other neurodegenerative conditions with cell-specific pathologies such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS).