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A Tau Biomarker Is Detected in Blood Before the Clinical Onset of Alzheimer's Symptoms

Article In Brief

A biomarker for phosphorylated tau—p-tau123—was detected earlier than two other tau biomarkers in the blood of people with early pre-clinical Alzheimer's disease.

A biomarker for phosphorylated tau—p-tau231—was detected in the plasma of people in the early pre-clinical stages of Alzheimer's disease (AD), according to a study published in February in Acta Neuropathologica.

The tau biomarker is the third to be detected in the past year; p-tau 181 and p-tau 217 have also been tested and detected in people who already have symptoms of AD.

“By the time someone has symptoms, and is being worked up for AD, all three of these tau blood biomarkers work equally well,” said Nicholas J. Ashton, PhD, assistant professor at the University of Gothenburg in Sweden, who led the study with Kaj Blennow, MD, PhD, professor of neurochemistry.

“What is novel about this [p-tau231] blood biomarker, which was actually identified in cerebrospinal fluid [CSF] two decades ago, is that it arrives on the scene earlier,” Dr. Ashton said. “We do not yet know [exactly] how early this epitope comes online, but it is clear that it is there well before people develop symptoms of AD.”

These tau blood biomarkers are only useful in identifying AD, and not in other non-AD dementias, Dr. Ashton pointed out, and the plasma p-tau231 was able to differentiate people across the Braak staging spectrum.

The p-tau231 biomarker could be used to enroll the right patients for studies of experimental AD therapies, and may help in diagnosing people in the earliest stages of the disease, the researchers said.

Dr. Ashton said recent technological advances made it possible to count single molecules of p-tau231 and quantify them in blood. In addition, he said, the AD PET technology made it possible to tease out the differences between these p-tau epitopes.

Study Design, Findings

The scientists first studied the tau biomarkers in the CSF of participants of the Translational Biomarkers of Aging and Dementia (TRIAD) cohort at McGill University. People in this study include healthy controls as well as patients in early through moderate stages of AD. They detected p-tau231 in the CSF from many people who would go on to develop AD.

With evidence that tau-p123 was detected earlier than the other two phosphorylated tau biomarkers, the investigators decided to use an ultra-sensitive digital biomarker technology—Simoa (a single molecule assay)—to look for this marker in blood.

After an initial confirmation that the newly developed assay could detect AD in a small discovery study, they returned to the same people they tested in the CSF study who already had blood stored, as well as amyloid and tau PET scans that are increasingly more common in large AD cohorts. They compared all three of the phosphorylated tau biomarkers and followed their evolutionary changes over time. Again, p-tau231 showed up earlier.

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“If you asked me five years ago if we could develop reliable blood tests I probably would not have been optimistic. But we have seen tremendous progress.”—DR. GIL D. RABINOVICI

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“These biomarkers have a real place in primary care settings to rule out Alzheimers in someone having cognitive problems.”—DR. NICHOLAS J. ASHTON

The investigators had confirmed autopsy cases whose blood showed evidence of this p-tau231 biomarker eight years earlier, before symptoms appeared. They also replicated their findings in several other smaller AD cohorts, including one in a primary care setting where people were thought to have AD but had not yet had a beta-amyloid PET scan. In total, they tested p-tau231 in blood from 588 people in these four independent cohorts. In all of them, the plasma p-tau231 levels were about two-fold higher in AD than in healthy controls or those elderly people who were negative for amyloid-beta.

The research team is now conducting follow-up studies to confirm the p-tau231 changes first in longitudinal studies and then in familial AD cohorts. “We now have the technology to quantify it, and it appears to be an earlier biomarker and more abundant in blood than the other p-tau epitopes,” said Dr. Ashton.

The big question is whether these biomarkers are ready for clinical use. And if this p-tau231 is a pre-clinical red flag, should it be used before there are treatments that could push back the disease process?

Dr. Ashton thinks not. “These biomarkers have a real place in primary care settings to rule out Alzheimer's in someone having cognitive problems,” he said, adding that the field will have to decide “which p-tau biomarker should be used to identify the first clinical signs in people who are developing Alzheimer's. It's amazing that we can detect these changes with a simple blood test. Blood is such an accessible tool and that is why the technology is moving forward so quickly. “But he added this caveat: “We have only used it in well-characterized situations. We need to test it in the clinic to see how well it performs in real life.”

Expert Commentary

“The current study reports the first ultrasensitive immunoassay for accurate quantification of the plasma p-tau231 marker,” said Verna R. Porter, MD, FANA, director of the programs for Alzheimer's disease, dementia and neurocognitive disorders, and professor of translational neurosciences and neurotherapeutics at Saint John's Cancer Institute, and clinical professor of neurology (emeritus and ongoing voluntary) at UCLA department of neurology.

“This recent publication (and other meeting presentations) suggest growing evidence that increases in plasma p-tau181, p-tau217, and p-tau231 occur soon after amyloid-beta starts to accumulate in the brain. This is notable since it is years before neurofibrillary tangles can be detected by tau-PET imaging, and likely decades before clinical symptoms arise.”

“These markers also appear to be capable of distinguishing AD from other forms of dementia,” she pointed out, “and are more robust measures of disease than those tests based on amyloid-beta pathology because they display a notably broader range over time—phosphorylated fragments of tau increase by as much as 10-fold in the blood as AD evolves, whereas the Aβ42/40 ratio decreases by about 15 percent at most.”

Dr. Porter added that “the hope is for the development of a CLIA-certified blood test to help clinicians detect and confirm the presence of Alzheimer's disease pathology, thereby allowing for earlier treatment interventions and access to research-based protocols. This type of testing will likely not be a stand-alone diagnostic, but will instead be used in the clinical context of assessing normal aging and cognitive/brain health.

“The ability to use this biomarker (plasma p-tau-231) to distinguish AD from non-AD dementias including primary tauopathies—for example, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration—may prove to be one of its major clinical uses,” Dr. Porter continued.

“Further, this particular biomarker (p-tau231) was able to differentiate individuals across the Braak stage spectrum, which was not the case for other plasma biomarkers (for example, p-tau181). The early and marked increase in p-tau231 also has important implications for therapeutic trials of drugs, which are increasingly focused on recruiting patients in the earliest possible stages of disease (under the threshold of amyloid-beta positivity and early tau deposition) where disease modification may be most possible.”

Gil D. Rabinovici, MD, FAAN, the Edward Fein & Pearl Landrith distinguished professor in the departments of neurology, radiology and biomedical imaging at University of California, San Francisco, called the use of effective blood tests to identify AD biomarkers “game-changers for the field. If you asked me five years ago if we could develop reliable blood tests I probably would not have been optimistic. But we have seen tremendous progress.”

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“The ability to use this biomarker (plasma p-tau-231) to distinguish AD from non-AD dementias including primary tauopathies—for example, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration—may prove to be one of its major clinical uses.”—DR. VERNA R. PORTER

Dr. Rabinovici said that currently the biomarker could be used to establish if AD might be a contributing factor in patients who have established cognitive impairment (mild cognitive impairment or dementia). “I would not use it to screen people without symptoms or with subjective concerns only,” he said. “Blood biomarkers are quite new and we don't know how they will predict future development of cognitive impairment.”

Dr. Rabinovici added that it may be useful in the future to use a panel of these blood biomarkers to help determine the staging of tau pathology in an individual, and it will be useful to have additional markers for amyloid- beta and neurodegeneration.

“Blood and CSF offer advantages over imaging because we can look at more than one protein at a time,” added Dr. Rabinovici. But he stressed that imaging is important, especially with tau, because it “tracks with symptoms and shows you where tau is” and where it spreads over the course of the disease.

Link Up for More Information

• Ashton NJ, Pascoal TA, Karikari TK, et al. Plasma p-tau231: A new biomarker for incipient Alzheimer's disease pathology https://link.springer.com/article/10.1007/s00401-021-02275-6. Acta Neuropathol 2021; Epub 2021 Feb 14.