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A novel blood test that detects a key biomarker for Alzheimer’s disease (AD) could help physicians more accurately determine the presence and track disease progression.

The test measures levels of the protein MTBR-tau243 — microtubule-binding region of tau containing the residue 243 — a biomarker of tau tangles in the brain that may be a more accurate measure of tau pathology than other established biomarkers.

Investigators used the test to successfully distinguish between patients at different stages of AD progression and identify whether cognitive decline was likely due to AD or some other cause.

“This blood test clearly identifies Alzheimer’s tau tangles, which is our best biomarker measure of Alzheimer’s symptoms and dementia,” study investigator Randall J. Bateman, MD, professor of neurology at Washington University School of Medicine, St. Louis, said in a press release.

“In clinical practice right now, we don’t have easy or accessible measures of Alzheimer’s tangles and dementia, and so a tangle blood test like this can provide a much better indication if the symptoms are due to Alzheimer’s and may also help doctors decide which treatments are best for their patients,” he added.

The research was published online on March 31 in Nature Medicine.

Novel Test Measures Tau

AD can be confirmed clinically through identification of tau pathology using tau PET, but researchers said a more accessible test is needed for clinical practice. Fluid biomarkers are an attractive alternative because of their accessibility and affordability, investigators noted.

As previously reported by Medscape Medical News, Bateman and his colleagues have developed two other blood tests for AD that identify amyloid plaques in the brain. But there currently are no blood tests that measure tau in the brain.

Building on findings presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, and reported by Medscape Medical News, investigators measured plasma MTBR-tau243 levels in individuals in the Swedish BioFINDER-2 cohort (n = 108) and the Charles F. and Joanne Knight Alzheimer Disease Research Center cohort (n = 55). They used a larger cohort from Swedish BioFINDER-2 (n = 739) to validate the results.

Across all three groups, which consisted of patients at every stage of AD, there were elevated plasma MTBR-tau243 levels that increased as the level of dementia increased. Plasma MTBR-tau243 itself also carried a strong and linear correlation with tau PET in areas of the brain with intermediate (P < .001) and late tau accumulation (P < .001) compared with two other known biomarkers, p-tau217 and p-tau205.

“I believe we will use blood-based p-tau217 to determine whether an individual has Alzheimer’s disease, but MTBR-tau243 will be a highly valuable complement in both clinical settings and research trials,” Co-senior Author Oskar Hansson, MD, PhD, a professor of neurology at Lund University in Lund, Sweden, said in the press release.

“When both of these biomarkers are positive, the likelihood that Alzheimer’s is the underlying cause of a person’s cognitive symptoms increases significantly, compared to when only p-tau217 is abnormal. This distinction is crucial for selecting the most appropriate treatment for each patient,” Hansson added.

Accurate disease staging could help clinicians select the most appropriate therapies for their patients, investigators noted.

“For early stages with low tau tangles, anti-amyloid therapies could be more efficacious than in late stages,” Kanta Horie, PhD, co-author and researcher at WashU Medicine, said in the press release. “But after the onset of dementia with high tau tangles, antitau therapy or one of the many other experimental approaches may be more effective.”

“Once we have a clinically available blood test for staging, plus treatments that work at different stages of the disease, doctors will be able to optimize their treatment plans for the specific needs of each patient,” he added.

The technology has been licensed to C2N Diagnostics, which was cofounded by Bateman and study co-author David Holtzman, MD, Washington University School of Medicine. The company plans to make the test available before the end of the year, Horie said.

Research, Clinical Implications

Commenting for Medscape Medical News, Gregory S. Day, MD, associate professor of neurology at the Mayo Clinic College of Medicine, who was not involved with the research said the results are another step toward noninvasive biomarkers for AD that are accessible and assess neuropathologic change.

“MTBR-tau243 offers particularly promise for detecting, and potentially even tracking, tau neuropathology in our research participants, with clear implications for staging disease for clinical trials,” he said.

“In the clinic, MTBR-tau243 may also improve our confidence in ruling in or out a diagnosis of Alzheimer’s disease in symptomatic patients — particularly older patients in whom biomarkers of amyloid alone lacks specificity,” he added.

For clinical trials, MTBR-tau243 could serve as a potential surrogate marker for a drug effect, which can be done through tau PET today but “the associated costs, infrastructural requirement, and exposure to radiation present clear limitations to broad integration of this technology in large, multicenter studies enrolling thousands of patients,” Day said.

In the clinic, the biomarker can be used to assess clinical response to US Food and Drug Administration approved therapies, or perhaps to identify patients with a greater need for support or supervision in the future, he said.

“This information is of high value to patients, families, and other caregivers who place high value on information that may inform rates of progression or progression, and future plans,” Day added.

Also commenting on the research Jason Krellman, PhD, assistant professor of neuropsychology at Columbia University Irving Medical Center in New York City, said that although it is a promising blood biomarker, diagnosing AD using a patient’s clinical presentation, symptoms, and progression in the era before biomarker and functional neuroimaging studies have historically been enough.

“Early detection of diseases with no available cures carries a lot of ethical and clinical challenges and questions,” said Krellman, who was not part of the study.

Further research should be conducted to determine how it performs in individuals with more diverse neurological or psychiatric conditions, he said. In addition, the blood test required a large amount of plasma for the diagnostic test and was better at identifying AD in its later vs earlier stages.

“This might not be an ideal test for very early detection in its current form,” Krellman said.

Need for Standardization 

With several promising blood tests for AD, a key question is “whether we need one of them, all of them, or the most consistent one across populations,” William Hu, MD, PhD, chief of cognitive neurology and the Alzheimer’s disease clinic at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, told Medscape Medical News.

“Blood tests for Alzheimer’s disease have been heavily promoted to doctors and the public, but their roll-out has not been smooth due to inconsistent tests and standards,” said Hu, who also was not involved in the research.

“Fewer steps necessary to measure a blood protein level will make standardization a lot more straightforward, and the process to measure MTBR-tau243 is more complex than other tests,” he added.

Some of the pitfalls have included the blood-brain barrier affecting the number of brain proteins in the blood, and patient factors like kidney and heart disease.

“[T]he technical challenge in standardizing blood collection/testing means it is very difficult to translate general patterns seen in large groups of people, where a lot of technical noise is tolerable, to the real world where a decision needs to be made for a single person,” Hu said.

Day also noted there are limitations to its potential application.

“Biofluid biomarkers, by nature, reflect steady-state levels of a protein at a point in time, and may be affected by procedural factors” such as how the fluid is obtained, handled, and stored, as well as through methodological constraints, he said.

Another consideration is that biofluid biomarkers do not show where proteins are accumulating in the brain. “For these reasons, I view this development as complementary to tau positron emission tomography and other neuroimaging-based biomarkers,” he said.

“These factors will need to be further explored as we consider how to apply and generalize these findings beyond research cohorts,” Day said.

Some authors reported personal and institutional relationships in the form of grants, corporate sponsorships, speaker’s bureau and advisory board positions, equity ownerships, research grants, paid employment, and consultancies for a variety of pharmaceutical companies, health technology companies, and other organizations, which include AbbVie, ADDF, ALZpath, Asteroid, Avid Radiopharmaceuticals, BioArctic, Biogen, Bristol Myers Squibb, Cajal Neurosciences, C2N Diagnostics, Denali, Eisai, Eli Lilly, Fujirebio, GE Healthcare, Genentech, Janssen, Merck, Novo Nordisk, Novartis, Roche, Siemens, and Switch. This study was supported by grants, awards, funding, and other resources from the Charles F. and Joanne Knight Alzheimer Disease Research Center, the Tracy Family SILQ Center, the National Institutes of Health, the Alzheimer’s Association, the Hope Center for Neurological Disorders, and the department of neurology at WashU Medicine. Hu reported being a consultant for Fujirebio Diagnostics, Beckman Coulter, and Siemens Healthineers that are developing blood tests for Alzheimer’s disease. Krellman and Day reported no relevant financial relationships.