Novel Form of Tau Protein Found in Spinal Fluid Indicates Stage of Alzheimer’s Disease
December 7, 2020

A novel form of the tau protein, found in cerebrospinal fluid, can confirm the stage of Alzheimer’s disease by indicating how much tau pathology is in the brains of patients, according to a study published in the journal Brain.

The discovery of so-called microtubule binding region tau (MTBR tau) in the cerebrospinal fluid could lead to a way to diagnose people in the earliest stages of Alzheimer’s disease, before they have symptoms or when their symptoms are still mild and easily misdiagnosed. It also could accelerate efforts to find treatments for the devastating disease, by providing a relatively simple way to gauge whether an experimental treatment slows or stops the spread of toxic tangles.

“This MTBR tau fluid biomarker measures tau that makes up tangles and can confirm the stage of Alzheimer’s disease by indicating how much tau pathology is in the brains of Alzheimer’s disease patients,” said senior author Randall J. Bateman, MD, Washington University Medical Campus, St. Louis, Missouri. “If we can translate this into the clinic, we’d have a way of knowing whether a person’s symptoms are due to tau pathology in Alzheimer’s disease and where they are in the disease course, without needing to do a brain scan. As a physician, this information is invaluable in informing patient care, and in the future, to guide treatment decisions.”

Tau tangles can be detected by positron emission tomography (PET) brain scans, but brain scans are time-consuming, expensive and not available everywhere. MTBR tau is an insoluble piece of the tau protein, and the primary component of tau tangles.

Dr. Bateman and colleagues realised that specific MTBR tau species were enriched in the brains of people with Alzheimer’s disease, and that measuring levels of the species in the cerebrospinal fluid that bathes the brain might be a way to gauge how broadly the toxic tangles have spread through the brain. Previous researchers using antibodies against tau had failed to detect MTBR tau in the cerebrospinal fluid, but the researchers developed a new method based on using chemicals to purify tau out of a solution, followed by mass spectrometry.

Using this technique, the researchers analysed cerebrospinal fluid from 100 people in their 70s. Of the individuals, 30 had no cognitive impairment and no signs of Alzheimer’s disease, 58 had amyloid plaques with no cognitive symptoms, or with mild or moderate Alzheimer’ dementia, and 12 had cognitive impairment caused by other conditions.

The researchers found that levels of MTBR tau 243 in the cerebrospinal fluid were elevated in the people with Alzheimer’s and that it increased the more advanced a person’s cognitive impairment and dementia were.

The researchers verified their results by following 28 members of the original group over 2 to 9 years. Half of the participants had some degree of Alzheimer’s at the start of the study. Over time, levels of MTBR tau 243 significantly increased in the Alzheimer’s disease group, in step with a worsening of scores on tests of cognitive function.

To see how their technique matched up to the gold standard (tau-PET brain scan), the researchers compared the amount of tau visible in brain scans of 35 people (20 with Alzheimer’s disease and 15 without) with levels of MTBR tau 243 in the cerebrospinal fluid. MTBR tau 243 levels were highly correlated with the amount of tau identified in the brain scan, suggesting that their technique accurately measured how much tau -- and therefore damage -- had accumulated in the brain.

“Right now there is no biomarker that directly reflects brain tau pathology in cerebrospinal fluid or the blood,” said first author Kanta Horie, PhD, Washington University School of Medicine. “What we’ve found here is that a novel form of tau, MTBR tau 243, increases continuously as tau pathology progresses. This could be a way for us to not only diagnose Alzheimer’s disease but tell where people are in the disease. We also found some specific MTBR tau species in the space between neurons in the brain, which suggests that they may be involved in spreading tau tangles from one neuron to another. That finding opens up new windows for novel therapeutics for Alzheimer’s disease based on targeting MTBR tau to stop the spread of tangles.”

Reference: https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaa373...

SOURCE: Washington University School of Medicine