Novel Alzheimer's Protein a 'Great Hope' for the Future

December 10, 2020

Dr Randall J. Bateman

A novel form of tau protein may be an accurate way to diagnose and track early Alzheimer's disease (AD), offering new hope for the future.

In a study of 100 participants, microtubule binding region tau (MTBR-tau) was identified in cerebral spinal fluid (CSF) — and its levels had a strong correlation with tau tangles in the brain.

"Until now, we haven't been able to measure the tau proteins associated with tau tangles from biomarkers in the CSF or blood," senior study investigator Randall J. Bateman, MD, professor of neurology, Washington University School of Medicine, St Louis, Missouri, told Medscape Medical News.

"But in this study, we show a tight and strong correlation between CSF levels of MTBR-tau and tau tangles in the brain," Bateman said.

The findings were published online December 7 in Brain.

Diagnostic Marker

Biomarkers currently used to measure tau in CSF and blood are phosphorylated forms of tau, "and these are not found in tau tangles in the brain, the pathology that correlates best with Alzheimer's symptoms," Bateman said.

"We have learned a lot from these biomarkers, but we now believe that these phosphorylated tau species are actually a reaction to amyloid plaques and are not actually associated with the tau that forms the tangles in the brain," he added.

In the current study, researchers report the identification and quantification of the novel MTBR-tau in CSF and report that it shows a high correlation to tau tangles found on PET imaging in the brains of patients with AD.

The investigators used sequential immunoprecipitation and chemical extraction methods followed by mass spectrometry to analyze levels of various forms of MTBR-tau in the CSF of individuals in their 70s.

Of the 100 participants, 30 had no cognitive impairment and no signs of AD, 58 had amyloid plaques, with no cognitive symptoms or with mild or moderate AD, and 12 had cognitive impairment caused by other conditions.

Results showed that levels of one specific form of tau found in CSF, MTBR-tau 243, were elevated in participants with AD and that it increased in line with cognitive impairment and dementia progression.

The researchers verified the results by following 28 members of the original study over a 2- to 9-year period. Half of participants had some degree of AD at study outset. Over time, levels of MTBR-tau 243 significantly increased in the AD group, which was in line with worsening cognitive function test scores.

The researchers also examined how CSF levels of MTBR-tau 243 matched up with the volume of tau tangles in PET scans of the brain in 35 individuals (20 with AD, 15 without). They found that MTBR tau 243 levels in CSF were highly correlated with the amount of tau identified on the brain scans.

A New Biomarker?

"If we are trying to track tau tangles, then we need a biomarker that correlates with tangles. MTBR-tau 243 could be that marker," Bateman said.

At present, the only way to track tau tangles is with a PET scan, which is very expensive and uses complicated equipment.

"What we really need is a blood test," said Bateman. Although it hasn't yet been ascertained that MTBR-tau can be measured in blood, the investigators are looking into that issue.

"Usually with substances that can be found in the CSF, it is also possible to measure them in the blood," said Bateman.

Although it is possible to measure phosphorylated forms of tau in the blood, it is now believed that these forms of tau are an adaptive response and not necessarily a pathology, he added.

Aggregated proteins in the brain are always pathogenic; and aggregated tau, in the form of tangles, correlates well with patients' symptoms, Bateman said. "It is more important than amyloid in respect to Alzheimer's symptoms."

Amyloid plaques can occur in the brain and be asymptomatic for decades. Tau appears at about the same time as symptoms develop and as dementia progress, tau tangles increase.

Bateman noted that the build-up of amyloid-beta is believed to be the start of the AD process and stimulates neurons to produce more tau.

"While some tau is needed in the brain — it has a physiological role stabilizing axons and neurons — for some reason the appearance of amyloid plaques causes an overproduction of tau and phosphorylation changes. This overproduction leads to the formation of tau deposits inside neurons which heralds the onset of Alzheimer's symptoms," he said.

"Great Hope"

In 2015, the investigators reported on a highly specific blood test for amyloid-beta.

"It is much more difficult to develop a blood test for a protein found mainly in the CSF," Bateman said. "We talk about 'the 50,000-fold problem.' The proteins are generally 50 times less concentrated in the blood than in the CSF and there are 1000 times as many other proteins in the blood to interfere with its measurement. So the amyloid blood test was a major breakthrough."

In 2019, the researchers published a study assessing phospho-tau in the blood, "and now we are reporting this finding of MTBR-tau in the CSF being a reliable measure of tau tangles," said Bateman.

"These are very exciting results. The number of markers we have for Alzheimer's is filling out very nicely," he added.

Bateman said that, in the future, there may be an AD panel of tests similar to a cholesterol panel.

In addition to amyloid-beta, phospho-tau, and MTBR-tau, another test for a marker of neurodegeneration such as neurofilament light chain may be added. Such a panel of markers would then give a comprehensive picture of AD and allow the disease stage to be mapped, Bateman noted.

"We could assess how likely it is that a person may develop Alzheimer's, how early on in the disease process they are if they don't have symptoms, what stage they are at if they do have symptoms, how fast is it progressing, and how they are reacting to various treatments," he said.

"While the MBTR-tau test is at the very early stages, this is just the first report. It presents great hope for the future," he added.  

The study was funded by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Foundation for Barnes-Jewish Hospital, the John and Linda Tracy Family, Coins for Alzheimer's Research Trust, and the Alzheimer's Association Research Fellowship. Bateman has reported equity ownership interest in C2N Diagnostics, receiving royalty income based on technology licensed by Washington University to C2N Diagnostics, and reported he may receive income based on further technology regarding diagnosing AD with phosphorylation changes. He has also reported receivin honoraria from AC Immune, Amgen, C2N Diagnostics, Eisai, Janssen, Pfizer, and Roche in his role as a speaker, consultant, and/or advisory board member.

Brain. Published online December 7, 2020. Full text  

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