A Better Tau Blood Test for Diagnosing Alzheimer's?

Pauline Anderson

July 28, 2020

Researchers are making headway in developing a blood test for the presence of tau, one of the hallmarks of Alzheimer's Disease (AD).

In one new development, experts at the University of California, San Francisco (UCSF) compared phosphorylated-tau181 (P-tau181) to a related form of tau called P-tau217 to determine which can best identify individuals with AD.

Results showed that the two biomarkers were similar overall, but P-tau 217 had a slight edge in terms of accuracy. Importantly, both tau isoforms distinguished frontotemporal lobar degeneration (FTLD).

"These new blood tests for P-tau are going to be really exciting because they will improve our ability to simply and inexpensively assess whether someone is at high risk for having Alzheimer's Disease," study author Adam L. Boxer, MD, PhD, professor in UCSF's Department of Neurology, told Medscape Medical News.

Dr Adam Boxer

With the approval of the first disease-modifying therapy for AD possibly around the corner, developing an accurate diagnostic blood test for this condition is even more urgent, added Boxer, who is also director of UCSF's Neurosciences Clinical Research Unit and AD and FTD Clinical Trials Program.

The findings were presented at the Alzheimer's Association International Conference (AAIC) 2020, which was held online this year because of the COVID-19 pandemic.

Important Implications

Currently, the only approved AD biomarkers are expensive positron emission tomography (PET) scans using agents that detect tau or amyloid, another hallmark AD protein, and cerebrospinal fluid levels of amyloid and tau, the measurement of which entails invasive lumbar puncture procedures.

This limits the ability to easily confirm the underlying cause of dementia or cognitive impairment, which "obviously has important prognostic and therapeutic implications," said Boxer.

Having a plasma biomarker, especially for tau, would be extremely useful. Patients with increased tau in the brain tend to exhibit AD symptoms while those with amyloid plaques do not always have clear signs, at least not immediately.

"We think that P-tau is probably a better measure because it's much more closely related to symptoms of disease," said Boxer.

Earlier this year, he and his colleagues published a study in Nature Medicine showing that P-tau181 is more than three times as high in individuals with AD compared with healthy elderly people. It also differentiated AD from FTD.

“We found that P-tau 181 was almost as good as a PET scan or lumbar puncture at identifying individuals with AD pathology in the brain,” said Boxer.

They next wanted to assess how well P-tau 217 held up as a possible biomarker.

The new retrospective study was comprised of 210 participants, including 37 who acted as healthy controls, 99 who had FTLD, 39 who had AD, and 35 who had mild cognitive impairment.

More Accurate Test

Results showed that plasma P-tau217 was increased 5.7-fold in the participants with AD compared with the healthy controls group, and increased fivefold compared with those who had FTLD (both comparisons, P < .001).

The increase in plasma P-tau181 was lower. It was increased only 4.5-times in participants with AD compared with the healthy controls and 3.8-times relative to those with FTLD (both, P < .001).

In addition, P-tau217 was potentially superior in predicting whether a person had a tau positive FTP-PET brain scan.

"This newer P-tau 217 test produces very similar results to the previous test we published [on P-tau181], but might be incrementally better or slightly more accurate, and even more closely related to the signal you get with a tau PET scan," Boxer said.

The researchers are now examining these issues in a larger group of participants (N = 617). Results for those analyses are expected to be published soon.

In addition to tau and amyloid markers, the researchers are also examining another potential biomarker of neurodegeneration: the triple protein neurofilament light chain.

It's too early to say which biomarker or biomarkers will prove to be the most useful in diagnosing AD, Boxer noted.

"It's an open question whether it will be necessary to measure multiple P-taus plus beta amyloid plus neurofilament, or maybe just measuring one P-tau level will be sufficient," he said.

Upcoming Therapy?

Having a test that verifies AD is becoming all the more important now that a therapy might soon be available. Massachusetts-based biotech company Biogen has submitted aducanumab, a monoclonal antibody that targets amyloid-beta (Aβ), to the US Food and Drug Administration for approval.

Should that move forward, aducanumab would be the first disease-modifying therapy for AD.

"If that's the case, it will be even more important to have simple ways to screen people, to see if they might eventually be eligible for treatment," said Boxer.

Even if the drug isn't approved, many patients simply want to know what is causing their cognitive problems, he added.

Knowing they have AD might impact their life planning. If they have mild symptoms, interventions such as exercise and reducing cardiovascular risk could improve their overall health and quality of life, he said.

If individuals have another type of dementia, such as FTLD, that, too, might determine a different approach.

Some forms of FTLD are caused by "completely different biological processes," which are now being studied, Boxer said. So knowing that patients have this condition would allow them to participate in relevant clinical trials.

Exciting Aspect

Having a tau blood test will also help those in underserviced and minority communities who can't easily access memory specialists, Boxer noted.

"It might allow them to access care, and get help much more easily, and that's a really exciting aspect of this new technology," he said.

It's not clear when such blood tests will be on the market, although many companies are "scrambling" to make them available, said Boxer.

P-tau217 also holds promise as a marker for early AD pathology, according to another study presented at AAIC 2020.

The Swedish research team measured P-tau217 in more than 1000 participants, including those who were unimpaired and those with mild cognitive impairment, AD dementia, and non-AD neurodegenerative diseases.

Results showed that plasma P-tau217 levels increase in early stages of AD when insoluble tau aggregates are not yet detectable with PET. They also predict subsequent increases in tau-PET, as well as conversion to AD dementia.

"Incredible Breakthrough"

Commenting on the research for Medscape Medical News, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer's Drug Discovery Foundation, called the study amazing and "an incredible breakthrough."

"Researchers are able to detect disease up to 20 years before symptoms. The blood test has very good characteristics in terms of sensitivity and specificity. It correlates with the spinal fluid, it's better than the PET imaging, it correlates with the amyloid test, and the results are being confirmed in many different cohorts," said Fillit, who was not involved with the research.

A tau blood test, especially for P-tau 217, has the potential to be as important to determining dementia risk as cholesterol is to gauging heart disease risk, he added.

Having a tau blood test will "make our clinical trials much more precise and more efficient and reduce costs tremendously," Fillit said, adding that he thinks tau blood tests might come to market as early as within a year.

Also commenting for Medscape Medical News, Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer's Association, said the new studies illustrate the rapid progress being made "in the blood biomarker space."

Even 5 years ago, researchers would "never have thought" that blood biomarkers could be used as a tool to detect brain changes related to AD, said Edelmayer.

These new studies are "filling a gap in our understanding around tau" in AD and other neurodegenerative diseases, she said. "Being able to distinguish between diseases is going to be very, very crucial for clinicians in the future," she added.

Edelmayer foresees that in the future there will be a panel of blood biomarkers in addition to imaging tests to help clinicians make an accurate diagnosis.

The study was supported by the National Institutes of Health and the Tau Research Consortium. Boxer disclosed that the blood p-tau test was done as part of a research collaboration between UCSF and Eli Lilly. Fillit and Edelmayer have disclosed no relevant financial relationships.

Alzheimer's Association International Conference (AAIC) 2020: Abstract # 45755. Presented July 28, 2020.

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