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.
Researchers have been exploring the role metabolites play in the development of disease for some time. Alzheimer’s is a progressive, degenerative brain disease typically linked to age, family history, and deposits of certain proteins in the brain that cause the brain to shrink and brain cells to eventually die. Alzheimer’s is the most common form of dementia, accounting for an estimated 60% to 80% of all dementia cases. It has no cure or proven method of prevention, according to the Alzheimer’s Association.
There are nearly seven million people living with Alzheimer’s in the US and 55 million people worldwide live with it or other forms of dementia. Patients are usually over the age of 65, but it can present in younger patients as well.
“Gut metabolites are the key to many physiological processes in our bodies, and for every key there is a lock for human health and disease,” said Feixiong Cheng, PhD (above), founding director of the Cleveland Clinic Genome Center, in a news release. “The problem is that we have tens of thousands of receptors and thousands of metabolites in our system, so manually figuring out which key goes into which lock has been slow and costly. That’s why we decided to use AI.” Findings from the study could lead to new clinical laboratory biomarkers for dementia screening tests. (Photo copyright: Cleveland Clinic Lerner Research Institute.)
Changes to Gut Bacteria
Metabolites are substances released by bacteria when the body breaks down food, drugs, chemicals, or its own tissue, such as fat or muscle. They fuel cellular processes within the body that may be either helpful or harmful to an individual’s health.
The Cleveland Clinic researchers believe that preventing detrimental interactions between metabolites and cells could aid in disease prevention. Previous studies have shown that Alzheimer’s patients do experience changes in their gut bacteria as the disease progresses.
To complete their study, the scientists used AI and machine learning (ML) to analyze more than 1.09 million potential metabolite-receptor pairs to determine the likelihood of developing Alzheimer’s.
They then examined genetic and proteomic data from Alzheimer’s disease studies and looked at different receptor protein structures and metabolite shapes to determine how different metabolites can affect brain cells. The researchers identified significant interactions between the gut and the brain.
They discovered that the metabolite agmatine was most likely to interact with a receptor known as CA3R in Alzheimer’s patients. Agmatine is believed to protect brain cells from inflammation and damage. They found that when Alzheimer’s-affected neurons are treated with agmatine, CA3R levels reduce. Levels of phosphorylated tau proteins, a biomarker for Alzheimer’s disease, lowered as well.
The researchers also studied a metabolite called phenethylamine. They found that it too could significantly alter the levels of phosphorylated tau proteins, a result they believe could be beneficial to Alzheimer’s patients.
New Therapies for Alzheimer’s, Other Diseases
One of the most compelling results observed in the study was the identification of specific G-protein-coupled receptors (GPCRs) that interact with metabolites present in the gut microbiome. By focusing on orphan GPCRs, the researchers determined that certain metabolites could activate those receptors, which could help generate new therapies for Alzheimer’s.
“We specifically focused on Alzheimer’s disease, but metabolite-receptor interactions play a role in almost every disease that involves gut microbes,” said Feixiong Cheng, PhD, founding director of the Cleveland Clinic Genome Center in the news release. “We hope that our methods can provide a framework to progress the entire field of metabolite-associated diseases and human health.”
The team plans to use AI technology to further develop and study the interactions between genetic and environmental factors on human health and disease progression. More research and studies are needed, but results of the Cleveland Clinic study suggest new biomarkers for targeted therapies and clinical laboratory tests for dementia diseases may soon follow.
Findings could lead to clinical laboratory tests that help physicians identify microbes lacking in the microbiomes of their Parkinson patients
Microbiologists and clinical laboratory scientists know that gut microbiome can be involved in the development of Parkinson’s disease, a progressive neurological disorder that affects the nervous system due to damage caused to nerve cells in the brain. There is no cure for the illness. But a new treatment developed by researchers at the VIB Center for Inflammation Research at the University of Ghent in Belgium, may help to alleviate the symptoms.
During a clinical trial, VIB Center for Inflammation Research (VIB-IRC) scientists discovered that fecal microbiota transplantation (FMT), also known as a stool transplant, can improve motor skills in some Parkinson’s patients, according to Neuroscience News.
Parkinson’s disease (PD) develops when a protein called alpha-synuclein misfolds and forms into bundled clusters damaging nerve cells in the brain that produce dopamine. These formations, which are believed to appear in the gastrointestinal wall in the early stages of PD, then reach the brain via the vagus nerve leading to typical PD symptoms in patients.
“Our study provides promising hints that FMT can be a valuable new treatment for Parkinson’s disease,” Roosmarijn Vandenbroucke, PhD (above), Principal Investigator, VIB-UGent Center for Inflammation Research and full professor, UGent Department of Biomedical molecular biology, Faculty of Sciences, told Neuroscience News. “More research is needed, but it offers a potentially safe, effective, and cost-effective way to improve symptoms and quality of life for millions of people with Parkinson’s disease worldwide.” Clinical laboratories will likely be involved in identifying the best microbes for the FMT treatments. (Photo copyright: University of Ghent.)
Correlation between Gut Microbiome and Neurogenerative Disease
To perform their clinical study—referred to as GUT-PARFECT—the IRC researchers first recruited patients with early-stage PD and healthy donors who provided stool samples to the Ghent Stool Bank. The PD patients received the healthy stool via a tube inserted into the nose which led directly into the small intestine.
The FMT procedures were performed on 46 patients with PD between December 2020 and December 2021. The participants in this group ranged in ages from 50 to 65. There were 24 PD patients in the placebo group, and a total of 22 donors provided the healthy stool. Clinical evaluations were performed at baseline, three, six, and 12 months.
After 12 months, the group that received the transplants showed a reduction in symptoms compared to the placebo group. Their motor score on the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) improved by a mean of 5.8 points. The improvement registered on the same scale for the placebo group was 2.7 points.
Developed in the 1980s, the MDS-UPDRS is a scale utilized to evaluate various aspects of PD by measuring patient responses via a questionnaire rating several issues (such as cognitive impairment, apathy, depression, and anxiousness) common in PD patients from normal to severe. It is divided into four parts:
Part I: Non-motor experiences of daily living.
Part II: Motor experiences of daily living.
Part III: Motor examination.
Part IV: Motor complications.
During the final six months of the research, the improvement in motor symptoms became even greater. To the VIB-IRC researchers this implied that an FMT may have long-lasting effects on PD patients. The FMT study group also experienced less constipation, a condition that can be bothersome for some PD patients.
“Our results are really encouraging!” said the study’s first author, Arnout Bruggeman, MD, PhD student, VIB-UGent Center for Inflammation Research, in a UGent News release. “After twelve months, participants who received the healthy donor stool transplant showed a significant improvement in their motor score, the most important measure for Parkinson’s symptoms.”
Findings Could Lead to Other Targeted Therapies for PD
The VIB-IRC researchers believe there is a correlation between the gut microbiome and Parkinson’s disease.
“Our findings suggested a single FMT induced mild, but long-lasting beneficial effects on motor symptoms in patients with early-stage PD. These findings highlight the potential of modulating the gut microbiome as a therapeutic approach and warrant a further exploration of FMT in larger cohorts of patients with PD in various disease stages,” the IRC researchers wrote in eClinicalMedicine.
“Our next step is to obtain funding to determine which bacteria have a positive influence. This could lead to the development of a ‘bacterial pill’ or other targeted therapy that could replace FMT in the future,” Debby Laukens, PhD, Associate Professor, Ghent University, told Neuroscience News.
According to the Parkinson’s Foundation website, nearly one million people in the US live with PD. It is second only to Alzheimer’s disease in the category of neurodegenerative diseases.
More research and studies are needed before the VIB-IRC’s stool transplant treatment can be used in clinical care. As researchers learn more about which specific strains of bacteria are doing the beneficial work in PD patients, that data could eventually lead to clinical laboratory tests performed to help physicians identify which microbes are lacking in the microbiomes of their PD patients, and if fecal transplants could help those patients.
New non-invasive test could replace traditional painful spinal taps and clinical laboratory fluid analysis for diagnosis of Parkinson’s disease
Scientists at AXIM Biotechnologies of San Diego have added another specimen that can be collected non-invasively for rapid, point-of-care clinical laboratory testing. This time it is tears, and the diagnostic test is for Parkinson’s disease (PD).
The new assay measures abnormal alpha-synuclein (a-synuclein), a protein that is a biomarker for Parkinson’s, according to an AXIM news release which also said the test is the first rapid test for PD.
“The revolutionary nature of AXIM’s new test is that it is non-invasive, inexpensive, and it can be performed at a point of care. It does not require a lumbar puncture, freezing, or sending samples to a lab. AXIM’s assay uses a tiny tear drop versus a spinal tap to collect the fluid sample and the test can be run at a doctor’s office with quantitative results delivered from a reader in less than 10 minutes,” the news release notes.
“Furthermore, emerging evidence shows that a-synuclein assays have the potential to differentiate people with PD from healthy controls, enabling the potential for early identification of at-risk groups,” the news release continues. “These findings suggest a crucial role for a-synuclein in therapeutic development, both in identifying pathologically defined subgroups of people with Parkinson’s disease and establishing biomarker-defined at-risk cohorts.”
This is just the latest example of a disease biomarker that can be collected noninvasively. Other such biomarkers Dark Daily has covered include:
“With this new assay, AXIM has immediately become a stakeholder in the Parkinson’s disease community, and through this breakthrough, we are making possible new paradigms for better clinical care, including earlier screening and diagnosis, targeted treatments, and faster, cheaper drug development,” said John Huemoeller, CEO, AXIM (above), in a news release. Patients benefit from non-invasive clinical laboratory testing. (Photo copyright: AXIM Biotechnologies.)
Fast POC Test versus Schirmer Strip
AXIM said it moved forward with its novel a-synuclein test propelled by earlier tear-related research that found “a-synuclein in its aggregated form can be detected in tears,” Inside Precision Medicine reported.
But that research used what AXIM called the “outdated” Schirmer Strip method to collect tears. The technique involves freezing tear samples at -80 degrees Celsius (-112 Fahrenheit), then sending them to a clinical laboratory for centrifugation for 30 minutes; quantifying tear protein content with a bicinchoninic acid assay, and detecting a-synuclein using a plate reader, AXIM explained.
Alternatively, AXIM says its new test may be performed in doctors’ offices and offers “quantitative results delivered from a reader in less than 10 minutes.”
“Our proven expertise in developing tear-based diagnostic tests has led to the development of this test in record speed, and I’m extremely proud of our scientific team for their ability to expand our science to focus on such an important focus area as Parkinson’s,” said John Huemoeller, CEO, AXIM in the news release.
“This is just the beginning for AXIM in this arena,” he added. “But I am convinced when pharmaceutical companies, foundations, and neurologists see how our solution can better help diagnose Parkinson’s disease in such an expedited and affordable way, we will be at the forefront of PD research, enabling both researchers and clinicians a brand-new tool in the fight against PD.”
One of those tests was “a lateral flow diagnostic for point-of-care use that measures the level of lactoferrin proteins in tear fluid, which work to protect the surface of the eye. … Axim said that low lactoferrin levels have also been linked to Parkinson’s disease and that the assay can be used alongside its alpha-synuclein test,” Fierce Biotech noted.
“It made sense to try and look at the proteinaceous [consisting of or containing protein] constituents of tear fluid,” Lew told Neurology Live. “Tear fluid is easy to collect. It’s noninvasive, inexpensive. It’s not like when you do a lumbar puncture, which is a much more involved ordeal. There’s risk of contamination with blood (saliva is dirty) issues with blood and collection. [Tear fluid analysis] is much safer and less expensive to do.”
In Biomarkers in Medicine, Lew et al noted why tears make good biomarkers for Parkinson’s disease, including “the interconnections between the ocular [eye] surface system and neurons affected in Parkinson’s disease.”
The researchers also highlighted “recent data on the identification of tear biomarkers including oligomeric α-synuclein, associated with neuronal degeneration in PD, in tears of PD patients” and discussed “possible sources for its release into tears.”
Future Clinical Laboratory Testing for Parkinson’s
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s. It affects nearly one million people in the US. About 1.2 million people may have it by 2030, according to the Parkinson’s Foundation.
Thus, an accurate, inexpensive, non-invasive diagnostic test that can be performed at the point of care, and which returns clinical laboratory test results in less than 10 minutes, will be a boon to physicians who treat PD patients worldwide.
Clinical laboratory managers and pathologists may want to follow AXIM’s future research to see when the diagnostic test may become available for clinical use.
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.
