By Paul Nicolaus
March 18, 2019 | New research reveals that a blood test could help detect the progression of Alzheimer’s disease up to 16 years before the onset of symptoms, which scientists say could open doors for the testing of therapies.
Before visible symptoms of Alzheimer’s set in, the brain begins to change and neurons start to degrade. When brain cells die, their remnants can be found in the blood. Typically, proteins degrade quickly and are, in turn, not particularly useful as a marker of neurodegenerative disease. One exception is a piece of neurofilament that is resistant to deterioration.
In their study, published January 21 in Nature Medicine (doi: 10.1038/s41591-018-0304-3), an international group of researchers led by Mathias Jucker of the German Center for Neurodegenerative Diseases and the Hertie Institute for Clinical Brain Research measured this protein fragment in the blood and used it as a readout for neuron loss and neurodegeneration.
“We can measure in the blood what’s happening in the brain,” he told Diagnostics World News.
The findings rely on data from over 400 individuals that were analyzed within an international research collaboration called the Dominantly Inherited Alzheimer Network (DIAN), which investigates families impacted by a rare form of Alzheimer’s disease that causes memory loss and dementia at earlier ages than the more common form of the disease due to inherited gene mutations. A parent with this type of mutation has a one in two chance of passing the genetic abnormality to a child.
The 243 patients carrying the gene mutations that predispose them to Alzheimer’s disease were found to have greater neurofilament levels than the control group made up of 162 family members who do not carry the mutations. In a prospective study, the researchers also found a link between 39 individuals’ changing neurofilament levels and the loss of brain mass and cognitive decline that occurred two years later. Together, the findings indicate that changes in neurofilament levels can be an early predictor of the disease and help forecast how brain damage develops over time.
Higher levels of neurofilament can also stem from other neurodegenerative disorders or brain injuries, however, so the blood test is not necessarily specific to Alzheimer’s disease. “This is not diagnostic,” Jucker cautioned. “The most significant finding is that we have something in the blood which is a readout for nerve cell loss in the brain.”
It is not the absolute neurofilament concentration but rather its evolution that enables predictions about the future progression of the disease. Although the rate of change in neurofilament concentration was closely linked to brain degradation, correlation with the build-up of amyloid proteins was less pronounced. The finding supports the assumption that even though amyloid proteins are triggers of the disease, neuronal deterioration takes place independently.
Moving forward, there are plans to build upon the recently published findings. It is not yet apparent, for example, over what period of time the rate of change in protein levels needs to be calculated. Is it enough to take blood every other month, for example? Do samples need to be taken over the course of a full year? “This is not very clear,” Jucker said, so further refinements are needed to validate the test and make it useful beyond a clinical trial setting.
Measuring Biomarkers at Lower Concentrations
The research conducted by Jucker and colleagues was carried out using Simoa, a Quanterix platform that monitors protein levels in blood and makes it possible to identify single molecules of biomarkers that are indicative of disease progression such as Alzheimer’s.
“Simoa allows researchers to identify single molecules of biomarkers in the blood that are indicative of diseases across therapeutic areas, including neurology, oncology, cardiology, inflammation, and infectious disease,” Kevin Hrusovsky, president and CEO of Quanterix said in an email to Diagnostics World News. The technology encompasses two distinct platforms, each with a different technical approach to measuring protein biomarkers for different types of applications.
“The original Simoa technology is based upon the isolation of individual immunocomplexes on paramagnetic beads,” he explained. “Individual molecules are trapped in femtoliter-sized wells, allowing for a ‘digital’ readout of each individual bead to determine if it is bound to the target analyte or not.” The next generation Simoa planar technology uses a slightly different approach but can provide similar performance while allowing for the measurements of multiple markers at the same time.
Simoa is able to measure individual proteins at concentrations 1,000 times lower than conventional assays allow for, according to Hrusovsky, which he said can be likened to finding one blade of grass in a field the size of Alaska or finding one grain of sand in 2,000 Olympic-size swimming pools. From a practical perspective, what this means is that certain biomarkers that could previously be measured only in cerebrospinal fluid with a lumbar puncture can now be measured with a simple blood test as a small amount of these markers make their way from the brain into the blood.
This type of sensitivity makes it possible to see Alzheimer’s earlier in the disease cascade and determine that a blood test could be a reliable way of detecting its progression years ahead of symptoms. The ability to see biomarkers at minute concentrations means that sick patients can be diagnosed, Hrusovsky added, but it also means that baseline changes in healthy patients can be monitored, which is the first step toward transitioning from today’s sick-care into preventative healthcare.
Simoa is currently utilized by researchers in a variety of settings, from academic and government labs to pharmaceutical and drug development companies, and the technology is being used to study a number of other neurodegenerative diseases, such as multiple sclerosis, Parkinson’s, and traumatic brain injuries. While the commercial kit has not garnered regulatory clearance for diagnostic use, Hrusovsky indicated that the company aims to bring this technology to a diagnostic setting and make it available at point-of-care in the years ahead.
To get there, researchers will need to determine how much protein in the blood is considered too much and figure out how quickly protein levels can rise before there is cause for concern.
Blood Biomarkers Showing Promise
One of the hallmarks of Alzheimer’s disease is the build-up of beta-amyloid in the brain, a process thought to begin decades before any signs of dementia reveal themselves. Current tests for beta-amyloid have drawbacks, however. The current gold standard in clinical research is an expensive amyloid PET scan or an invasive lumbar puncture, and diagnosis is often made without these tools, relying instead on the assessment of a patient’s symptoms.
To reach the goal of widespread screening for the earliest indication of Alzheimer’s disease, non-intrusive, less expensive, and highly reliable biomarkers are needed, according to Anton P. Porsteinsson, professor of psychiatry and neurology, and director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester Medical Center. “Blood biomarkers are emerging as the most promising solution,” he said in an email to Diagnostics World News. “These include plasma amyloid, tau, and neurofilament light.”
The promise of the recent Nature Medicine study is that it reveals the possibility of following neurofilament as a predictor of disease progression, he explained, which means it could extend beyond diagnostics and into the realm of therapy research. One key limitation, however, is that this study was carried out using participants that are at a high risk of developing a rare familial type of the disease that makes up less than 1% of total Alzheimer’s cases.
Even though this was a relatively large, longitudinal study, added Sarah C. McEwen, director of research and programming at the Pacific Neuroscience Institute’s Brain Health Center at Providence Saint John’s Health Center, this means that the “results may not necessarily be generalizable to individuals who do not hold this same genetic risk,” she said in an email to Diagnostics World News. “The study needs replication in a much larger, longitudinal population-based sample.”
Another caveat is that higher levels of neurofilament can stem from other neurodegenerative disorders, too, so the blood test is not necessarily specific to this one disease, McEwen explained. To validate the prognostic value of the assay, it would be important to discriminate for Alzheimer’s disease using a machine learning approach across patient populations.
Big “Ifs” Remain
The statistics are staggering, said Keith Fargo, director of scientific programs & outreach at the Alzheimer’s Association. In the United States alone, nearly 6 million Americans are living with Alzheimer’s disease, and it is one of the costliest conditions to society. It is estimated that over a quarter of a trillion dollars were devoted to the direct costs of caring for Americans with this disease last year.
“It’s a huge problem,” he told Diagnostics World News, “but we don’t have a blood test for it yet.” That’s why the recent Nature Medicine study is “potentially a significant development,” Fargo said, but we don’t really know just yet. In addition to the cautions voiced by Porsteinsson and McEwen, another lingering uncertainty is that there are other potential blood tests currently under development.
According to Fargo, the one that is probably the furthest along right now—it’s already in clinical trials—focuses on amyloid in the blood, which is more specific to Alzheimer’s disease than neurofilament. It came about through research (doi: 10.1016/j.jalz.2017.06.2266) funded in part by the Alzheimer’s Association and carried out by a group at Washington University School of Medicine in St. Louis. That study was led by Randall J. Bateman, who was also involved in the recently published Nature Medicine research.
So will these new findings from Jucker and colleagues upend the status quo? Not yet, according to Fargo, although it is possible further down the road if the amyloid test doesn’t work out as hoped or if the neurofilament test turns out to be a superior blood test. “But it’s just way too early to know that yet,” he added.
The next step is to see if it is useful in the larger population of people that have sporadic Alzheimer’s. If it does work in that population and in some basic studies, the next step is to move on to clinical trials, and that will take a number of years. Those are a couple of big ifs, he added, and “until those questions are answered, it’s not going to change practice now.”
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com