New clinical laboratory test could replace conventional spinal tap for diagnosing neurodegenerative disease
In a proof-of-concept study, University of Pittsburgh (Pitt) scientists validated a clinical laboratory test that measures more than 100 different genetic sequences associated with Alzheimer’s disease. The Pitt researchers believe the new diagnostic platform could help clinicians “capture the multifaceted nature of Alzheimer’s pathology and streamline early disease diagnostics,” according to a news release.
Clinical laboratory blood tests that detect biomarkers such as phosphorylated tau protein (pTau) have emerged in studies as diagnostic possibilities for Alzheimer’s disease, which is traditionally diagnosed using a lumbar puncture (spinal tap) procedure.
In their paper, neuroscientist Thomas Karikari, PhD, Assistant Professor of Psychiatry at University of Pittsburgh, lead author of the study, and his research team acknowledged that progress has been made in detecting Alzheimer’s disease with blood-based biomarkers. However, they note that “two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction.”
The Pitt scientists believe the focus on so-called “classical Alzheimer’s blood biomarkers” limits exploration of neurodegenerative disease.
“Alzheimer’s disease should not be looked at through one single lens. Capturing aspects of Alzheimer’s pathology in a panel of clinically validated biomarkers would increase the likelihood of stopping the disease before any cognitive symptoms emerge,” said neuroscientist Thomas Karikari, PhD (above), Assistant Professor of Psychiatry, University of Pittsburgh, and lead author of the study in a news release. Should further studies prove Pitt’s research sound, clinical laboratories may have a replacement test for diagnosing neurodegenerative disease. (Photo copyright: University of Pittsburgh.)
On its website, Alamar Biosciences explains that the disease panel offers neurological researchers:
“Multiplexed analysis of 120 neuro-specific and inflammatory proteins from 10 µl of plasma or CSF (cerebrospinal fluid).
Detection of “critical biomarkers—including pTau-217, GFAP (glial fibrillary acidic protein), NEFL (neurofilament light polypeptide) and alpha-synuclein.”
The NULISAseq test works with “a proprietary sequential immunocomplex capture and release mechanism and the latest advances in next-generation sequencing,” according to the company.
Inside Precision Medicine noted that the Alamar Biosciences assay enabled Pitt scientists to detect:
Biomarkers (usually found in CSF) “correlating with patients’ amyloid positivity status and changes in amyloid burden over time,” and,
Biomarkers including “neuroinflammation, synaptic function, and vascular health, which had not previously been validated in blood samples.”
“The performance of the NULISA platform was independently validated against conventional assays for classic Alzheimer’s biomarkers for each sample. Biomarker profiles over two years were also compared with imaging-based measures of amyloid, tau, and neurodegeneration,” LabMedica reported.
Opportunity to Track Alzheimer’s
Karikari sees the diagnostic platform being used to track individuals’ blood biomarker changes over time.
In their Molecular Neurodegeneration paper, the Pitt researchers wrote, “These (results) were not limited to markers such as pTau217, p-Tau231, p-Tau181, and GFAP, the elevation of which have consistently shown strong associations with brain Aβ [amyloid beta] and/or tau load, but included novel protein targets that inform about the disease state of the individual in different pathological stages across the biological Alzheimer’s disease continuum.”
About seven million Americans are affected by Alzheimer’s disease, according to the Alzheimer’s Association, which estimated that figure will grow to 13 billion by 2050.
Further studies by Karikari may include larger samples and greater diversity among the people studied, Inside Precision Medicine noted.
“[Karikari’s] lab is developing a predictive model that correlates biomarker changes detected using NULISAseq with brain autopsy data and cognitive assessments collected over the course of several years. Their goal is to identify blood biomarkers that can help stage the disease and predict its progression, both for decision-making around clinical management and treatment plans,” the Pitt news release states.
The Pitt scientists have developed a multiplex test that works with 100 different genetic sequences associated with Alzheimer’s. Such advances in the understanding of the human genome are giving scientists the opportunity to combine newly identified gene sequences that have a role in specific disease states.
In turn, as further studies validate the value of these biomarkers for diagnosing disease and guiding treatment decisions, clinical laboratories will have new assays that deliver more value to referring physicians and their patients.
As new diagnostic assays are cleared by regulators, clinical laboratories will play a key role in identifying appropriate patients for new less-invasive Alzheimer’s tests
With multiple companies racing to develop a blood-based test for Alzheimer’s disease (AD), clinical laboratories may soon have new less-invasive diagnostic assays for AD on their menus.
Why a race? Because a less-invasive clinical laboratory test that uses a venous blood draw (as opposed to a spinal tap)—and which has increased sensitivity/specificity—has a potentially large market given the substantial numbers of elderly predicted to develop Alzheimer’s over the next decade. It has the potential to be a high volume, high dollar diagnostic test.
In fact, Mordor Intelligence estimates that the market for Alzheimer’s disease therapeutics will grow from $7.7 billion in 2024 to $10.10 billion by 2029.
Alzheimers.gov, an official website of the US government, says, “Researchers have made significant progress in developing, testing, and validating biomarkers that detect signs of the disease process. For example, in addition to PET scans that detect abnormal beta-amyloid plaques and tau tangles [abnormal forms of tau protein] in the brain, NIH-supported scientists have developed the first commercial blood test for Alzheimer’s. This test and others in development can not only help support diagnosis but also be used to screen volunteers for research studies.”
Additionally, the US Food and Drug Administration (FDA) is clearing new Alzheimer’s drugs for clinical use. The pharma companies behind these drugs need clinical laboratory tests that accurately diagnosis the disease and confirm that it would be appropriate for the patient to receive the new therapeutic drugs, a key element of precision medicine.
“The big promise for blood tests is that they will eventually be accessible, hopefully, cost-effective, and noninvasive,” Rebecca Edelmayer, PhD (above), Vice President, Scientific Engagement, Alzheimer’s Association, told USA Today. “The field is really moving forward with use of these types of tests,” she added. Clinical laboratories may soon have these new assays on their test menus. (Photo copyright: Alzheimer’s Association.)
Companies in the Race to Develop Blood-based Alzheimer’s Tests
Researchers found that C2N’s blood test can detect brain amyloid status with “sensitivity, specificity, positive and negative predictive values that approximate those of amyloid positron emission tomography (PET) imaging,” according to a news release.
“The PrecivityAD2 blood test is intended for use in patients aged 55 and older with signs or symptoms of mild cognitive impairment or dementia who are undergoing evaluation of Alzheimer’s disease or dementia. Only a healthcare provider can order the PrecivityAD2 test,” the news release noted.
“The PrecivityAD2 blood test showed strong clinical validity with excellent agreement with brain amyloidosis by PET,” the researchers wrote.
The PrecivityAD2 test, which is mailed directly by C2N to doctors and researchers, is performed at the company’s CLIA-certified lab, according to USA Today, which added that the cost of $1,450 is generally not covered by insurance plans.
Expanding Test Access with IVD Companies
ALZpath, Inc. has a different approach to the Alzheimer’s disease test market. The Carlsbad, Calif.-based company, set up an agreement with in vitro diagnostics (IVD) company Roche Diagnostics for use of its phosphorylated tau (pTau)217 antibody “to develop and commercialize an Alzheimer’s disease diagnostic blood test that will be offered on the Roche Elecsys platform,” according to a news release.
Roche received FDA breakthrough device designation on the Elecsys pTau217 test earlier this year and will work with pharmaceutical company Eli Lilly to commercialize the test.
Estimates show 75% of dementia cases go undetected—a number which could grow to 140 million by 2050, according to data shared by Roche with Fierce Biotech.
“We plan to leverage our installed base of diagnostic systems, which is the largest in the world, to ensure we are able to create access to this test for those who need it the most,” Matt Sause, CEO, Roche Diagnostics, told Fierce Biotech.
Another IVD company, Beckman Coulter, recently signed an agreement to use ALZpath’s pTau217 antibody test in its DxI 9000 Immunoassay Analyzer. In a news release, Kathleen Orland, SVP and General Manager of the Clinical Chemistry Immunoassay Business Unit at Beckman Coulter, said that the test had “high performance in detecting amyloid pathology” and could “integrate into our advanced DxI 9000 platform to support broad-based testing.”
Clinical Laboratory Participation
The FDA is drafting new guidance titled, “Early Alzheimer’s Disease: Developing Drugs for Treatment” that is “intended to assist sponsors in the clinical development of drugs for the treatment of the stages of sporadic Alzheimer’s disease (AD) that occur before the onset of overt dementia.”
Pharma companies intent on launching new drugs for Alzheimer’s will need medical laboratory tests that accurately diagnosis the disease to confirm the medications would be appropriate for specific patients.
Given development of the aforementioned pTau217 antibody tests, and others featuring different diagnostic technologies, it’s likely clinical laboratories will soon be performing new assays for diagnosing Alzheimer’s disease.
Already-existing clinical laboratory blood test may be new standard for detecting Alzheimer’s biomarkers
In Sweden, an independent study of an existing blood test for Alzheimer’s disease—called ALZpath—determined that this diagnostic assay appears to be “just as good as, if not surpass, lumbar punctures and expensive brain scans at detecting signs of Alzheimer’s in the brain,” according to a report published by The Guardian.
Alzheimer’s disease is one of the worst forms of dementia and it affects more than six million people annually according to the Alzheimer’s Association. Clinical laboratory testing to diagnose the illness traditionally involves painful, invasive spinal taps and brain scans. For that reason, researchers from the University of Gothenburg in Sweden wanted to evaluate the performance of the ALZpath test when compared to these other diagnostic procedures.
Motivated to seek a less costly, less painful, Alzheimer’s biomarker for clinical laboratory testing, neuroscientist Nicholas Ashton, PhD, Assistant Professor of Neurochemistry at the University of Gothenburg, led a team of scientists that looked at other common biomarkers used to identify changes in the brain of Alzheimer’s patients. That led them to tau protein-based blood tests and specifically to the ALZpath blood test for Alzheimer’s disease developed by ALZpath, Inc., of Carlsbad, Calif.
In their JAMA article, they wrote, “the pTau217 immunoassay showed similar accuracies to cerebrospinal fluid biomarkers in identifying abnormal amyloid β (Aβ) and tau pathologies.”
In an earlier article published in medRxiv, Ashton et al wrote, “Phosphorylated tau (pTau) is a specific blood biomarker for Alzheimer’s disease (AD) pathology, with pTau217 considered to have the most utility. However, availability of pTau217 tests for research and clinical use has been limited.”
Thus, the discovery of an existing pTau217 assay (ALZpath) that is accessible and affordable is a boon to Alzheimer’s patients and to the doctors who treat them.
“The ALZpath pTau217 assay showed high diagnostic accuracy in identifying elevated amyloid (AUC, 0.92-0.96; 95%CI 0.89-0.99) and tau (AUC, 0.93-0.97; 95%CI 0.84-0.99) in the brain across all cohorts. These accuracies were significantly higher than other plasma biomarker combinations and equivalent to CSF [cerebrospinal fluid] biomarkers,” an ALZpath press release noted.
“This is an instrumental finding in blood-based biomarkers for Alzheimer’s, paving the way for the clinical use of the ALZpath pTau217 assay,” stated Henrik Zetterberg, MD, PhD (above), Professor of Neurochemistry at the University of Gothenburg and co-author of the study. “This robust assay is already used in multiple labs around the globe.” Clinical laboratories may soon be receiving doctors’ orders for pTau217 blood tests for Alzheimer’s patients. (Photo copyright: University of Gothenburg.)
Study Details
Ashton’s team conducted a cohort study that “examined data from three single-center observational cohorts.” The cohorts included:
“Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023,” the researchers wrote.
These trials from the US, Canada, and Spain featured 786 participants and featured “either a lumbar puncture or an amyloid PET scan to identify signs of amyloid and tau proteins—hallmarks of Alzheimer’s disease,” The Guardian reported, adding that results of the University of Gothenburg’s study showed that the ALZpath pTau217 blood test “was superior to brain atrophy assessments, in identifying signs of Alzheimer’s.”
“80% of individuals could be definitively diagnosed on a blood test without any other investigation,” Ashton told The Guardian.
Diagnosis Needed to Receive Alzheimer’s Disease Treatments
“If you’re going to receive [the new drugs], you need to prove that you have amyloid in the brain,” Ashton told The Guardian. “It’s just impossible to do spinal taps and brain scans on everyone that would need it worldwide. So, this is where the blood test [has] a huge potential.”
Even countries where such drugs were not yet available (like the UK) would benefit, Ashton said, because the test, “Could potentially say that this is not Alzheimer’s disease and it could be another type of dementia, which would help to direct the patient’s management and treatment routine.”
However, Ashton himself noted the limitations of the new findings—specifically that there is no success shown yet in Alzheimer’s drugs being taken by symptom-free individuals.
“If you do have amyloid in the brain at 50 years of age, the blood test will be positive,” he said. “But what we recommend, and what the guidelines recommend with these blood tests, is that these are to help clinicians—so someone must have had some objective concern that they have Alzheimer’s disease, or [that] their memory is declining,” he told The Guardian.
Experts on the Study Findings
“Blood tests could be used to screen everyone over 50-years old every few years, in much the same way as they are now screened for high cholesterol,” David Curtis, MD, PhD, Honorary Professor in the Genetics, Evolution and Environment department at University College London, told The Guardian.
“Results from these tests could be clear enough to not require further follow-up investigations for some people living with Alzheimer’s disease, which could speed up the diagnosis pathway significantly in future,” Richard Oakley, PhD, Associate Director of Research and Innovation at the Alzheimer’s Society, UK, told The Guardian.
Though Oakley found the findings promising, he pointed out what should come next. “We still need to see more research across different communities to understand how effective these blood tests are across everyone who lives with Alzheimer’s disease,” he said.
“Expanding access to this highly accurate Alzheimer’s disease biomarker is crucial for wider evaluation and implementation of AD blood tests,” the researchers wrote in JAMA Neurology.
“ALZpath makers are in discussions with labs in the UK to launch it for clinical use this year, and one of the co-authors, Henrik Zetterberg, MD, PhD, Professor of Neurochemistry at the University of Gothenburg, is making the assay available for research use as part of the ‘biomarker factory’ at UCL,” The Guardian reported.
In the US, to be prescribed any of the available Alzheimer’s medications, a doctor must diagnose that the patient has amyloid in the brain. A pTau217 diagnostic blood test could be used to make such a diagnosis. Currently, however, the test is only available “for research studies through select partner labs,” Time reported.
“But later this month, doctors in the US will be able to order the test for use with patients. (Some laboratory-developed tests performed by certain certified labs don’t require clearance from the US Food and Drug Administration.),” Time added.
It may be that the University of Gothenburg study will encourage Alzheimer’s doctors in the UK and around the world to consider ordering pTau217 diagnostic blood tests from clinical laboratories, rather than prescribing spinal taps and brains scans for their Alzheimer’s patients.
