NEW YORK – A new blood-based biomarker for Alzheimer's disease, brain-derived tau (BD-tau), is drawing interest from both academic researchers and industry for its potential to refine and add to information provided by existing markers as well as possibly help guide treatment with anti-amyloid therapies.
In recent months, researchers at the University of Gothenburg have published studies on the protein's link to Alzheimer's disease, and immunoassay firm Quanterix has announced plans to bring an assay for the marker to market in the second quarter of the year. Other companies in the Alzheimer's biomarker space have also expressed interest in BD-tau as a marker for the disease.
Tau proteins are involved in the function of microtubules, but in certain neurodegenerative diseases including Alzheimer's, hyperphosphorylated and misfolded forms of the protein can form aggregates that have been linked to neurodegeneration. Total tau and phosphorylated tau levels are well established cerebrospinal fluid markers for aiding the diagnosis of Alzheimer's disease. More recently, blood-based biomarkers for Alzheimer's have received significant academic and industry interest as researchers have demonstrated the feasibility of detecting markers linked to the disease in patient blood.
Unlike cerebrospinal fluid or PET imaging tests for Alzheimer's, blood-based tests can be run inexpensively and at large scale. Recent US Food and Drug Administration approvals — in particular of Eisai's Alzheimer's drug Leqembi (lecanemab) — have raised the possibility that physicians will in the near future need easily scalable Alzheimer's screening methods to identify patients who may benefit from these and/or future treatments.
Phosphorylated-tau 217 (p-tau 217) has emerged as a promising blood-based marker for detecting the presence of the brain amyloid pathology characteristic of Alzheimer's disease. Evidence of brain amyloid pathology is required for treatment with anti-amyloid Alzheimer's drugs.
Not all patients with amyloid pathology progress to Alzheimer's disease and neurodegeneration, however, said Fernando Gonzalez-Ortiz, a doctoral student in the department of psychiatry and neurochemistry at the University of Gothenburg whose work has focused on Alzheimer's markers including BD-tau. He noted that while in CSF tau and p-tau provide good measures of neurodegeneration, blood-based markers for neurodegeneration are not as well established. He said he and his colleagues believe that blood-based BD-tau could help fill this gap, providing a tool to better stage the severity of patients' condition and possibly track their progression.
In a study published in April in Nature Communications, Gonzalez-Ortiz and colleagues, including Gothenburg professor and prominent Alzheimer's biomarker researcher Kaj Blennow (senior author on the paper), found that blood BD-tau was linked to CSF profiles (positive for amyloid pathology and elevated total tau) associated with more rapid cognitive decline in Alzheimer's patients and that it outperformed other markers of neurodegeneration, including neurofilament light chain and blood total tau.
"What we are trying to do with BD-tau is say that p-tau 217 is excellent for capturing amyloid pathology, but then if you add BD-tau to the mix … those who are [p-tau 217] positive and are also BD-tau positive are the ones who progress faster and show high rates of decline," Gonzalez-Ortiz said.
While tau is a well-known marker of brain injury, the protein is not brain specific. Forms of the protein, including some phosphorylated forms, are also produced by peripheral tissues, which means that blood-based tau measurements may also reflect tau biology outside the brain. The hope is that BD-tau will provide more brain-specific information because it does not include tau produced by peripheral systems. The rights to the anti-BD tau antibody used in the Gothenburg team's research are owned by UK firm Bioventix, which produced the antibody.
Joel Braunstein, CEO of Alzheimer's diagnostics company C2N Diagnostics, said that within Alzheimer's research "there is a lot of interest in looking at tau pathological markers" in hopes that they might provide information that is "helpful for disease staging or tracking clinical progression."
"Brain-derived tau has shown some interesting results with looking at rates of progression among people with established amyloid pathology," he said, though he noted that more work is required to determine whether and how the marker will prove most useful in this context. Braunstein said that C2N is exploring the marker microtubule binding region of tau, MTBR-tau, for similar purposes. The marker is meant to be specific to the tau tangles characteristic of neurodegenerative conditions including Alzheimer's. The company is developing CSF and plasma tests for the marker.
The Gothenburg study used Quanterix's Simoa immunoassay technology for making blood BD-tau measurements, and on the company's recent Q1 2024 earnings call, President and CEO Masoud Toloue said that it plans to release a BD-tau assay in Q2. In his remarks about the marker, Toloue focused less on its use as an independent marker of neurodegeneration and disease severity and more on its potential to improve the accuracy and sensitivity of the company's existing p-tau 217 test. While Quanterix's p-tau 217 assay has shown greater than 90 percent correlation with CSF and PET measurements of brain amyloid pathology, Toloue suggested that adding BD-tau could boost sensitivity and precision compared to a standalone p-tau 217 assay.
Quanterix declined requests for additional comments on its BD-tau plans.
Gonzalez-Ortiz noted that while many phosphorylated forms of tau like p-tau 217 are thought to be highly brain-specific, research has shown that "tau is actively being phosphorylated in peripheral organs."
"The idea is that if we can pair this [BD-tau antibody] with, for example, [p-tau] 217, we can improve the 217 assay to make it even more specific," Gonzalez-Ortiz said.
Braunstein suggested, however, that given the already excellent performance of p-tau 217 for detecting amyloid pathology and even early tau pathology, adding BD-tau to the mix needs to be evaluated for its clinical significance.
"It comes down to the question of what is the incremental benefit," he said.
C2N's p-tau 217 assay is different from Quanterix's in that it uses mass spectrometry as opposed to immunoassay. Additionally, the company's test measures the ratio of blood p-tau 217 to blood tau that is not phosphorylated at the 217 amino acid site, which it has found provides better performance for detecting brain amyloid pathology than measuring p-tau 217 alone.
Quanterix may be hoping the addition of a BD-tau assay will help it stay ahead of growing competition from other diagnostic companies that have recently released their own immunoassays for p-tau 217. Laboratory Corporation of America, Alzpath, and Quest Diagnostics have all brought clinical blood p-tau 217 immunoassays to market (though the Alzpath assay uses Quanterix's technology), while Roche has said it plans to submit a regulatory filing for such a test to the FDA in 2026. In April, Quanterix held an investor call in which Toloue said that companies offering these tests may be infringing on its intellectual property, though an IP expert contacted by 360Dx raised questions about the enforceability of those claims.
Quest indicated that it also is following developments around BD-tau, with Michael Racke, medical director for neurology at Quest, noting in an email that "we are aware of BD-tau and are investigating its potential for use in neurological testing."
He added that "current research supports BD-tau as a potential biomarker for total tau," but he also noted that p-tau 217 and p-tau 181 — which has shown usefulness for tracking disease progression — "also provide the necessary specificity for Alzheimer’s disease."
One other potential application of BD-tau within Alzheimer's could be to help detect side effects from treatment with anti-amyloid drugs like Eisai's Leqembi. Research by other Gothenburg scientists has shown that BD-tau levels are linked to stroke outcomes, and a main side effect of anti-amyloid drugs are amyloid-related imaging abnormalities, or ARIA, which include edema and hemorrhagic abnormalities that Gonzalez-Ortiz suggested BD-tau could help pick up. He said the researchers are currently looking for collaborations through which they could explore this idea.