Tau-based biomarker tracks Alzheimer's progression
Novel marker found in cerebrospinal fluid also could speed development of Alzheimer's drugs

Date:
July 13, 2023
Source:
Washington University School of Medicine
Summary:
Researchers have discovered a biomarker for Alzheimer's disease in
the cerebrospinal fluid known as MTBR-tau243 can be used to track
the progression of the disease and could speed drug development.


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FULL STORY ==========================================================================
Two pathologies drive the progression of Alzheimer's disease. Early on,
amyloid beta plaques lead the way, but around the time cognitive symptoms arise, tau tangles take over as the driving force and cognition steadily declines.

Tracking the course of the disease in individual patients has been
challenging because there's been no easy way to measure tau tangles in
the brain.

But now, researchers at Washington University School of Medicine in
St. Louis and Lund University in Lund, Sweden, have identified a form of
tau that could serve as a marker to track Alzheimer's progression. The
marker also could be used by Alzheimer's drug developers to assess whether investigational tau-based drugs -- the next frontier in Alzheimer's drug development -- are effective against the disease. Such drugs theoretically would benefit people in later stages of the disease, when tau tangles
play a crucial role.

By studying 667 people in Sweden and the U.S. at various stages of
Alzheimer's disease, the researchers discovered in the cerebrospinal
fluid that levels of a specific form of tau -- known as microtubule
binding region (MTBR)-tau243 - - track with the amount of damaging tau
tangles in the brain and with the degree of cognitive decline.

The findings, published July 13 in Nature Medicine, are a major step
toward a better approach to diagnosing and staging Alzheimer's disease. A
test based on MTBR-tau243 could speed up drug development by providing a relatively simple and inexpensive way to identify and monitor participants
in clinical trials and assess whether the experimental therapies,
including tau-based drugs, can change the course of the disease.

"This discovery provides biomarkers to specifically track the progression
of tau tangles, the major pathology that predicts dementia and cognition,
which is something that hasn't been within reach until now," said
co-senior author Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University. "These
findings will help accelerate drug development for patients with symptoms
of Alzheimer's disease.

We are also working on developing these biomarkers as a clinical test to
stage individual patients and improve patient care." The gold standard
for measuring tau tangles in the brain is the tau-positron emission
tomography (tau-PET) brain scan, which costs thousands of dollars and
requires expensive equipment and specialized expertise not available
at most hospitals, making such scans impractical for patient care and
costly for research studies.

In 2020, Bateman and Kanta Horie, PhD, a research associate professor
of neurology and co-first author on the new paper, showed that levels of
MTBR- tau243 in the cerebrospinal fluid reflect the amount of tau tangles
in the brain. In this new study, Bateman and Horie teamed up with Lund University's Oskar Hansson, MD, PhD, a professor of neurology and study co-senior author, and Gemma Salvado', PhD, a postdoctoral researcher
and co-first author, to extend the analysis to a larger number of people
and to compare MTBR-tau243 to other tau biomarkers.

The researchers analyzed data from people who volunteered for Alzheimer's research studies through the Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER)-2 (448 people) study in southern Sweden or the Knight Alzheimer Disease Research Center (219 people) in St.

Louis. The average age of participants was 71, and the group included
healthy people as well as people at all stages of disease, ranging from
those with some amyloid in their brains but no cognitive symptoms, to
those with extensive amyloid and tau in their brains and a diagnosis
of dementia. The researchers compared cognitive function with levels
of various forms of tau in the cerebrospinal fluid and with levels of
amyloid and tau in the brain, as measured by amyloid and tau PET scans.

Levels of MTBR-tau243 in the cerebrospinal fluid correlated strongly
with brain tau tangle levels and cognitive function. As MTBR-tau243
levels went up, tau levels in the brain also went up, and scores on
cognitive tests went down. In contrast, levels of another form of tau in
the cerebrospinal fluid, phosphorylated tau, tracked mainly with brain
amyloid levels but not with brain tau levels or cognitive function.

"To accurately diagnose Alzheimer's disease in patients with cognitive symptoms, we need biomarker-based evidence of both amyloid beta plaques
and tau tangle pathology," Hansson said. "With this new biomarker,
representing tau pathology, we can do this using a single cerebrospinal
fluid sample. This has the potential to clearly improve the diagnostic
as well as prognostic work-up of Alzheimer's worldwide. We hope that
we soon can do the same using a simple blood test." By combining the
two forms of tau in the cerebrospinal fluid -- phosphorylated tau and MTBR-tau243 -- the researchers were able to predict cognitive function
almost as well as by using tau-PET.

"A combination of phosphorylated tau and MTBR-tau243 in the cerebrospinal
fluid reveals not only whether an individual has Alzheimer's disease
but identifies the stage of illness -- from presymptomatic disease to full-blown dementia," Horie said.

By taking repeated samples of cerebrospinal fluid, researchers could track
the progression of the disease and determine the effect of interventions
such as experimental anti-tau therapeutics on the disease trajectory.

"In late stages of Alzheimer's disease, the effectiveness of anti-amyloid therapies may weaken because amyloid is no longer playing a major
role in driving the disease," Horie said. "But that's when tau becomes relevant. By stopping the tau pathology, we may be able to stop further cognitive decline including memory loss. By maintaining individuals at
the level of mild cognitive impairment and preventing further cognitive decline, we can help people maintain a good quality of life. That's what
we're working toward."
* RELATED_TOPICS
o Health_&_Medicine
# Alzheimer's_Research # Healthy_Aging # Elder_Care #
Diseases_and_Conditions
o Mind_&_Brain
# Dementia # Alzheimer's # Intelligence #
Disorders_and_Syndromes
* RELATED_TERMS
o Alzheimer's_disease o Drug_discovery o
Dementia_with_Lewy_bodies o Pharmaceutical_company o
Huntington's_disease o Mumps o Hodgkin's_lymphoma o
Personalized_medicine

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Materials provided by Washington_University_School_of_Medicine. Original written by Tamara Bhandari. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Kanta Horie, Gemma Salvado', Nicolas R. Barthe'lemy, Shorena
Janelidze,
Yan Li, Yingxin He, Benjamin Saef, Charles D. Chen, Hong Jiang,
Olof Strandberg, Alexa Pichet Binette, Sebastian Palmqvist,
Chihiro Sato, Pallavi Sachdev, Akihiko Koyama, Brian A. Gordon,
Tammie L. S. Benzinger, David M. Holtzman, John C. Morris,
Niklas Mattsson-Carlgren, Erik Stomrud, Rik Ossenkoppele, Suzanne
E. Schindler, Oskar Hansson, Randall J. Bateman. CSF MTBR-tau243
is a specific biomarker of tau tangle pathology in Alzheimer's
disease. Nature Medicine, 2023; DOI: 10.1038/ s41591-023-02443-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230713141940.htm

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