NEW YORK – Blood-based testing continues to expand within neurology as researchers and clinicians pursue less expensive and less invasive tools for diagnosing and managing neurodegenerative disease.
While Alzheimer's disease has taken up much of the attention in the space, conditions including Parkinson's disease and multiple sclerosis are also drawing interest as blood-based testing increasingly moves beyond its origins in cutting-edge research and into the laboratory and diagnostic mainstream.
The appeal of blood-based testing for neurology is straightforward. Blood is an easily accessible and commonly used sample type. Compared to other diagnostic tools often used in neurology, including imaging and cerebrospinal fluid testing (CSF), blood-based tests are typically less expensive and more widely distributed.
Historically, however, measuring neurology markers in blood has been challenging, especially in the case of markers reflecting disease biology within the brain. For instance, Alzheimer's markers like β-Amyloid (Aβ) and tau could be detected in CSF, but their low concentrations in blood made many question whether they could be measured reliably.
Given this limitation, much of the initial test development around these markers was done using advanced, research-use-only technologies. High-sensitivity immunoassay firm Quanterix, for instance, applied its Simoa technology to measuring blood-based neurology markers like neurofilament light chain (NfL) as well as Alzheimer's-linked forms of Aβ and tau. Meanwhile, neurology testing firm C2N Diagnostics developed an immunoprecipitation mass spectrometry-based workflow for measuring Aβ40 and Aβ42 in blood samples.
More recently, such assays have begun to migrate to more traditional clinical analyzers as larger in vitro diagnostic firms look to enter the space. Roche and Danaher subsidiary Beckman Coulter have announced plans to launch Alzheimer's IVDs that will measure plasma phosphorylated-tau 217 (p-tau 217). In September, Fujirebio Diagnostics filed its Lumipulse G pTau 217/β-Amyloid 1-42 Plasma Ratio in vitro diagnostic test with the US Food and Drug Administration (FDA) for possible approval or clearance.
For blood-based testing, Alzheimer's offers a massive potential market and a relatively clear use case, both of which account for its momentum in that disease area, said Viren Makhijani, an engagement manager at consulting firm Health Advances.
Currently, Alzheimer's blood testing is primarily focused on detecting the amyloid brain plaques linked to the disease, both to help clinicians make diagnoses and, potentially, to qualify individuals for treatment with disease modifying therapies directed against those plaques. FDA has approved two drugs for Alzheimer's — Biogen's Aduhelm (aducanumab) and Eli Lilly's Kisunla (donanemab) — both of which target brain amyloid plaques. To qualify for these treatments, patients must show evidence of amyloid brain pathology. At the moment, this is most commonly done via either PET imaging or CSF testing, but blood tests have demonstrated performance roughly equivalent to those methods.
In particular, plasma p-tau 217 has emerged as a promising biomarker for assessing whether a person has the amyloid brain pathology characteristic of Alzheimer's. Quest Diagnostics, Laboratory Corporation of America, C2N, and Quanterix have plasma p-tau 217 laboratory-developed tests (LDTs) on the market, while Roche and Beckman Coulter are developing p-tau 217 IVDs, as is Fujirebio.
Alzheimer's taking the lead
Robert Martone, scientific discipline director of neurology biomarkers at Labcorp, suggested that blood-based markers for better staging of Alzheimer's will become a growing area of activity. Earlier detection of the disease is also of interest, though he noted that the idea of testing asymptomatic individuals remains controversial. Guidelines published last year by the Alzheimer's Association identified a number of blood-based markers that could be of use for diagnosis, prognosis, staging, or assessing the effect of treatment. The organization cautioned against their use for evaluating asymptomatic patients, however.
Bresso, Italy-based Diadem is focused on this early detection space. The company's Alzosure Predict test uses mass spectrometry to measure plasma levels of a variant of the protein p53 that has been linked to Alzheimer's and which the company believes can detect the disease years prior to the appearance of amyloid pathology or symptom. In 2022, the company received breakthrough device designation from the FDA for the test as well as a $2.5 million grant from the US National Institutes of Health to validate the assay. In 2023, Quest licensed US rights to the test.
There is also a need for markers that can help clinicians distinguish between Alzheimer's and other causes of dementia, Martone said. He added that this is why Labcorp's ATN Profile blood test for Alzheimer's disease, which the company launched as a laboratory-developed test in 2023, includes NfL, which is not specific to Alzheimer's but is a more general marker of neurodegeneration.
"We constantly get the question, 'This is an assay for Alzheimer's disease, why do you include [NfL], which really isn't that informative for Alzheimer's disease?'" he said, noting that the inclusion of NfL is meant to identify individuals who, despite testing negative for Alzheimer's, may be experiencing neurodegeneration due to some other cause.
"Alzheimer's accounts for only 60 percent of dementias," Martone said. "We have good markers for it now. What's next is trying to differentiate between [Alzheimer's] and other dementias like Lewy body dementia or frontotemporal dementia. That's an area of focus for us."
Mark Frasier, CSO at the Michael J Fox Foundation, said that Alzheimer's blood markers could be informative across a range of neurological conditions.
"What we are seeing is that there is a lot of overlap between the pathologies that occur across diseases like Alzheimer's and Parkinson's and even [multiple sclerosis] and [amyotrophic lateral sclerosis]," he said. "There are tests that have really been analytically validated and, in some cases, clinical validated in diseases like Alzheimer's … that we are also using to understand … Parkinson's."
Frasier cited forms of tau like plasma p-tau 217 that are linked to brain amyloid pathology in Alzheimer's, noting that this amyloid pathology is often also present in individuals with Parkinson's disease or Lewy body dementia. MJFF is currently funding research using tau blood tests in its collection of longitudinal samples from Parkinson's patients to study the link between plasma tau levels and Parkinson's progression.
In January, C2N announced it had received a $1.5 million grant from MJFF to use its PrecivityAD2 Alzheimer's blood test — which measures Aβ42/Aβ40 ratio and p-tau217/N-p tau217 ratio — and its assay for microtubule binding region of tau (MTBR-tau) to study connections between Alzheimer's disease and Parkinson's disease, Lewy body dementia, and REM behavior disorder.
Parkinson's, Lewy body dementia, and REM behavior disorder are neuronal α-synucleinopathies, meaning that they stem from the formation of abnormal aggregates of the α-synuclein protein in the brain. San Francisco-based diagnostics firm Amprion offers an LDT for detecting abnormal αSyn in CSF to aid in the diagnosis of α-synucleinopathies. The Amprion test is what is known as an αSyn seed amplification assay (αSyn-SAA), which is based on the observation that misfolded αSyn protein induces misfolding and aggregation in healthy αSyn protein. In αSyn-SAAs, a sample containing patient αSyn is introduced to a collection of healthy αSyn proteins. If aggregates form, it is an indication that the patient sample contains misfolded αSyn.
Research is also ongoing into whether αSyn-SAAs can be conducted in blood to reliably detect misfolded αSyn protein. In 2023, Japanese researchers published a study in which they demonstrated detection of misfolded αSyn in blood.
Frasier said MJFF is funding several groups working on blood-based αSyn-SAAs.
"It's been shown by a couple of groups that they can do it in smaller academic labs, and the goal is now to make it reproducible and reliable," he said.
Frasier said MJFF and others are also looking at various modified forms of αSyn as potential biomarkers for Parkinson's and other α-synucleinopathies. He cited as one example Danish firm Nordic Bioscience's research into the use of blood-based Calpain-1-cleaved αSyn for monitoring disease progression and response to therapy.
By and large, Frasier said, blood testing for α-synucleinopathies is still in the research stage. There remains limited data on the usefulness of more established Alzheimer's blood markers in α-synucleinopathies, and while use of CSF αSyn-SAAs is growing within clinical trials, αSyn-SAAs in blood are not yet robust enough to see uptake, he said. An exception is NfL blood testing, which Frasier said is commonly used in clinical trials for Parkinson's treatments as it provides a general measure of neurodegeneration.
Monitoring MS in blood
NfL blood testing has also seen significant uptake in multiple sclerosis, both within clinical trials and for patient management. Health Advances' Makhijani noted that while Alzheimer's blood testing is understandably a hot topic, blood biomarkers have perhaps made even deeper inroads into MS to date.
In large part, he said, this is due to the many treatment options for the condition and the "general sense that we haven't yet optimized how we switch between drugs or escalate or de-escalate patients on those drugs."
Michael Sy, a neurologist at the University of California, Irvine College of Medicine, said that NfL and glial fibrillary acidic protein (GFAP) are currently the main blood-based markers in clinical use for MS. Octave Biosciences's proteomic Multiple Sclerosis Disease Activity (MSDA) blood test, which measures the levels of 18 proteins (including NfL and GFAP) to gauge disease activity, has also seen clinical uptake, Sy said.
Sy said these markers "are most useful as an additional data point when you're looking at someone." He noted that a patient's clinical report, neurological exam, and MRIs are in many cases not sufficient to provide a clear picture of an individual's status.
"Oftentimes there is discordance between the MRI and the clinical findings, for example," he said. "The MRI is showing something but the clinical findings don't corroborate it, or vice versa. So, it's nice to have an additional data point to help guide you."
Sy said that while he uses these blood tests quite routinely in his practice, uptake more broadly remains "somewhat limited."
"I think a lot of clinicians are not quite comfortable in terms of knowing what to do with these additional data points," he said. "You have to have some comfort level before you start making clinical decisions based on these numbers."
Sy said that one area blood markers could have a major impact in MS is in predicting disability progression in individuals with the disease. He said that while clinical exams and MRI are reasonably good at gauging disease activity, when it comes to predicting disability progression, "all of our current data is really bad actually."
"It's still very early days there," he said. "But having fluid biomarkers would hopefully really increase our sensitivity [for predicting] disability progression.
Uptake lags in TBI
Blood markers for traumatic brain injury also continues to be an area of interest to test developers. In October, Roche announced a collaboration with the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority (BARDA) to bring to market a blood test for more rapidly assessing individuals with suspected TBI. Companies including BioMérieux, Beckman Coulter, and Abbott are also active in the space.
Clinical uptake of blood-based TBI tests has been limited, however, Makhijani said. Doctors, he said, commonly choose to order CT scans out of caution if they have questions about whether a patient has suffered TBI. He added that if interventions are needed for TBI, they are typically "quite severe and need to be done quickly."
Looking to the future, Makhijani said he expects Alzheimer's will continue to dominate discussions of blood-based neurology markers.
"In Alzheimer's, [blood tests] are competing against PET scans, which are both costly and limited in terms of the centers that can perform it," he said. "Also, it gains you access to the only two approved drugs for the indication, so I think the use case is a little bit more clear" than it is in areas like MS.
Makhijani's Health Advances colleague Donna Hochberg added that Alzheimer's is a potentially much larger market than most other areas of neurology, which is "why the big guys have run at AD so quickly now that there is an indication that the tests will be used for." Roughly 7 million individuals in the US have Alzheimer's compared to roughly 1 million for MS. The number of Alzheimer's cases and individuals requiring evaluation for the disease are projected to grow as the populations ages.
Hochberg said, however, that a number of large IVD firms have NfL blood tests "on their to do list." Currently, testing for NfL is offered by Mayo Clinic, Labcorp, Quest Diagnostics, and Octave through its MSDA test. Labcorp also offers glial fibrillary acidic protein (GFAP) as part of its MS Monitoring Profile test, which it launched in January.
While large IVD firms and national labs have made major moves into blood-based neurology testing in recent years, Hochberg said she expects firms like Quanterix and C2N and their more specialized, higher-sensitivity technologies to continue to play major roles in the space.
"There are some use cases — NfL in MS, for example — where the clinical range is sort of above that [high sensitivity] threshold, but in other areas, particularly as you look at applications earlier in the disease pathway where concentrations are even lower, that high-sensitivity detection is really critical," she said.
Quanterix plans this year to launch a next-generation Simoa platform called Simoa One that company President and CEO Masoud Toloue said will provide a 10-fold increase in sensitivity compared to the current system while also offering "a substantial increase" in multiplexing.
"This next-generation technology is particularly valuable for neurodegenerative diseases, where detecting trace levels of p-tau, NfL, and other markers in blood could dramatically improve early intervention and monitoring," he said.
C2N, meanwhile, has announced plans to build a fully automated high-resolution mass spectrometry platform for running its assays, including its PrecivityAD blood tests. CEO Joel Braunstein has said that the system will be a true sample-to-answer instrument, with all steps of the sample prep, mass spec, and data reporting processes fully automated. The company expects to have a first-generation system in hand within the next several months.
Labcorp's Martone said that research and early development of new markers will naturally take place on research platforms like Quanterix's Simoa systems or mass spec, suggesting that it is less a matter of sensitivity than the fact that these platforms are open access and intended for experimentation, as opposed to the more locked down, high-throughput analyzers commonly used in clinical labs.
By and large, the latest clinical analyzers "have adequate sensitivity to handle these analytes," Martone said. "Initially, it was very problematic to get measures for [analytes like p-tau 217], but now it is routine for these platforms. They have been improved and are remarkably sensitive."
Commercialization hurdles
Regulatory and reimbursement challenges remain. Companies including BioMérieux and Abbott have received FDA 510(k) clearance for TBI assays, but otherwise neurology blood tests are largely offered as LDTs, which has limited uptake. In particular, a number of clinicians have said they are waiting on FDA approval before they will begin using Alzheimer's blood tests to evaluate patients for treatment with anti-amyloid therapies.
Alzheimer's testing also received a blow last year when the US Centers for Medicare and Medicaid Services (CMS) proposed a single-marker reimbursement rate for Alzheimer's markers of $17, which was well below what the industry had hoped for. Those markers have since been referred to the gapfill process, through which Medicare administrative contractors will set their own local rates.
Hochberg said that reimbursement has suffered from the fact that the assays priced thus far have largely been single-marker tests, which led CMS to determine reimbursement by cross-walking the single-marker general immunoassay rate of around $17 — an issue is not unique to neurology markers.
Moving forward, as more multi-marker tests come to market, reimbursement rates should better reflect the actual clinical utility of the tests, Hochberg said, though she cautioned that "companies commercializing these tests need to approach market access very carefully with strong clinical and economic data to ensure that the rates reflect value."