Measuring DNA from dead nerve cells may help diagnose Alzheimer’s
Novel technique requires only a blood test, may predict disease within 5 years
A novel technique that detects DNA from dead nerve cells in the blood may help diagnose Alzheimer’s disease and predict its development with a five-year window among people with mild cognitive impairment, a new study showed.
“Our research suggests that analyzing a simple blood draw can predict whether individuals with MCI [mild cognitive impairment] will develop Alzheimer’s disease within 5 years,” Timothy Jenkins, PhD, Resonant’s co-founder and the study’s senior author, said in a company press release.
“These data demonstrate significant potential for this technology’s use as a clinically actionable predictor of neurodegeneration, which could allow for pre-symptomatic interventions [or those before symptom onset],” Jenkins said, adding, “We believe that such early identification is the key to improving outcomes for patients with neurodegenerative disease.”
The study, “Detection of neuron-derived cfDNA in blood plasma: a new diagnostic approach for neurodegenerative conditions,” was published in Frontiers in Neurology.
Seeking to diagnose Alzheimer’s much earlier in its course
As more new treatments for Alzheimer’s become available, diagnosing the disease accurately and early has become increasingly important. Some studies have recently begun examining protein-based biomarkers such as amyloid-beta as potential diagnostic markers. But diagnosing Alzheimer’s remains challenging.
“Alzheimer’s disease has historically been diagnosed by cognitive symptoms and the presence of proteins called amyloid beta and tau, but by the time these symptoms appear, the disease has progressed too far to significantly alter its trajectory,” said Chad Pollard, Resonant’s co-founder and the study’s first author.
“We are determined to change this,” Pollard said.
To that end, the researchers explored an alternative diagnostic strategy looking at DNA in blood “that circumvents the limitations of protein-based assays,” they wrote.
When cells in the body die, their DNA is released into the blood, where it’s detectable in trace amounts. In neurodegenerative diseases like Alzheimer’s, this cell-free DNA, or cfDNA, would be expected to contain a high proportion of DNA from the dying neurons, or nerve cells.
Detecting cfDNA from dead neurons might therefore be a useful tool to diagnose Alzheimer’s at very early stages of the disease, the team hypothesized.
“Early pre-symptomatic diagnosis has the potential to revolutionize disease management, allowing interventions that could halt the disease’s progression altogether, significantly improving patient outcomes,” the researchers wrote.
“The use of cfDNA offers the advantage of convenient and minimally invasive sample collection compared to traditional cerebrospinal fluid [the liquid around the brain and spinal cord] or tissue biopsies, making this approach more accessible and patient friendly,” they added.
Alzheimer’s disease has historically been diagnosed by cognitive symptoms and the presence of proteins called amyloid beta and tau, but by the time these symptoms appear, the disease has progressed too far to significantly alter its trajectory.
Using cfDNA as a diagnostic biomarker presents a technical challenge however: how to distinguish between cfDNA from dying neurons and cfDNA from all the other types of cells dying in the body?
The scientists were able to solve this problem via a combination of detailed DNA sequencing and analysis of epigenetic changes.
Epigenetic modifications refer to the addition of chemical marks to DNA that influence genes’ activities without altering their underlying DNA sequence. Different types of cells characteristically have unique epigenetic profiles.
The team found that DNA from neurons show certain characteristic changes in methylation, a type of epigenetic modification, in particular regions of DNA. By looking at the proportion of DNA containing these methylation changes, the researchers were able to calculate the proportion of neuronal cfDNA.
“Through a comprehensive analysis of differential methylation regions (DMRs) between purified [brain] neurons and blood … samples, we identified robust biomarkers that accurately distinguish neuron-derived cfDNA from non-neuron derived cfDNA,” the team wrote.
Testing found to accurately ID ‘100% of patients’ with an Alzheimer’s diagnosis
Using this technology, the scientists analyzed blood samples from 13 Alzheimer’s patients, six people with MCI who progressed to confirmed Alzheimer’s within five years, six people with MCI who did not progress to Alzheimer’s, and 25 older people without signs of cognitive impairment.
The results showed that neuron-derived cfDNA accounted for more than 5% of the total cfDNA in all of the Alzheimer’s patients. In addition, all the people initially diagnosed with mild cognitive impairment who eventually progressed to Alzheimer’s, but only 25% of those who did not, had a proportion of neuronal cfDNA higher than 5%.
“Targeted sequencing at the identified DMR locus demonstrated that a conservative cutoff of 5% of neuron-derived cfDNA in blood … accurately identifies 100% of patients diagnosed with AD [Alzheimer’s disease], showing promising potential for early disease detection,” the team wrote.
“Additionally, this method effectively differentiated between patients with mild cognitive impairment (MCI) who later progressed to AD and those who did not, highlighting its prognostic capabilities,” they added.
The researchers speculated that the handful of MCI patients who had elevated neuron cfDNA levels but did not progress to Alzheimer’s might actually have been showing signs of early dementia, but they did not have access to data to verify this idea.
Among those without signs of cognitive impairment, just 10% had neuron-derived cfDNA accounting for more than 5% of total cfDNA.
“This cfDNA-based diagnostic strategy outperforms recently developed protein-based assays, which often lack accuracy and convenience,” the researchers wrote, adding that “this study highlights the advantages of utilizing cfDNA as a diagnostic tool for neurodegenerative diseases.”
Still, the team is working to increase the test’s cell-specificity and predictive power in people with mild cognitive impairment. Resonant aims to make the test broadly accessible, which “will be essential to see meaningful changes in patient care and outcomes,” Pollard said.