Information for Our Community

Whether you are part of our community or are interested in joining us, we welcome you to Washington University School of Medicine.

close  


Visit the News Hub

Tau-based biomarker tracks Alzheimer’s progression

Novel marker found in cerebrospinal fluid also could speed development of Alzheimer’s drugs

by Tamara BhandariJuly 13, 2023

Matt Miller

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. Such scans are approved by the Food and Drug Administration and may be covered by Medicare when used in patient care. They are available at major hospitals and academic medical centers such as Washington University. The researchers are hopeful that MTBR-tau243 could be developed as a low-cost, widely available blood or cerebrospinal fluid test to track Alzheimer’s progression as part of patient care and clinical trials. Previous research by Bateman’s group led to the development of an amyloid-based blood test for Alzheimer’s disease that is now clinically available.

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 Salvadó, 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 Charles F. and Joanne 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.”

Horie K, Salvadó G, Barthélemy NR, Janelidze S, Li Y, He Y, Saef B, Chen CD, Jiang H, Strandberg O, Pichet Binette A, Palmqvist S, Sato C, Sachdev P, Koyama A, Gordon BA, Benzinger TLS, Holtzman DM, Morris JC, Mattsson-Carlgren N, Stomrud E, Ossenkoppele R, Schindler SE, Hansson O, Bateman RJ. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease. Nature Medicine. July 13, 2023. DOI: 10.1038/s41591-023-02443-z

This work was supported by resources and effort provided by the Tracy Family SILQ Center; the Hope Center for Neurological Disorders; the Department of Neurology at Washington University School of Medicine; Eisai Co. Ltd.; the Charles F. and Joanne Knight Alzheimer Disease Research Center; the National Institutes of Health (NIH), grant number R01AG070941; the Swedish Research Council, grant number 2016-00906; the Knut and Alice Wallenberg Foundation, grant number 2017-0383, the Marianne and Marcus Wallenberg Foundation, grant number 2015.0125; the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University; the Swedish Alzheimer Foundation, grant number AF-939932; the Swedish Brain Foundation, grant number FO2021-0293; the Parkinson Foundation of Sweden, grant number 1280/20; the Cure Alzheimer’s Fund; the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; the Skåne University Hospital Foundation, grant number 2020-O000028; Regionalt Forskningsstöd, grant number 2020-0314; Swedish federal government under the ALF agreement, grant number 2018-Projekt0279; European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie action grant agreement No 101061836; and Gretaoch Johan Kocks research grants.

Kanta Horie is an Eisai-sponsored voluntary research associate professor at Washington University and has received salary from Eisai. Washington University. Randall Bateman and David Holtzman have equity ownership interest in C2N Diagnostics. Bateman and Holtzman receive income from C2N Diagnostics for serving on the scientific advisory board. Horie, Nicholas Barthélemy, Chihiro Sato and Bateman may receive income based on technology (Methods to Detect MTBR-tau Isoforms and use Thereof) (PCT/US2020/046224) licensed by Washington University to C2N Diagnostics. Hong Jiang and Holtzman may receive income based on technology (Anti-tau MTBR Antibodies and Methods to Detect Endogenously Cleaved Fragments of Tau and uses Thereof) (USSN 63/400,345) licensed by Washington University to C2N Diagnostics. Bateman is an unpaid scientific advisory board member of Roche and Biogen and receives research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis. Suzanne Schindler has analyzed data provided by C2N Diagnostics to Washington University, but she has not received any research funding or personal compensation from C2N Diagnostics. She has served on a scientific advisory board for Eisai. Holtzman is on the scientific advisory board of Genentech, Denali and Cajal Neurosciences and consults for Alector.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Children’s hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

Tamara covers infectious diseases, molecular microbiology, neurology, neuroscience, surgery, the Institute for Informatics, the Division of Physician-Scientists and the MSTP program. She holds a double bachelor's degree in molecular biophysics & biochemistry and in sociology from Yale University, a master's in public health from the University of California, Berkeley, and a PhD in biomedical science from the University of California, San Diego. She joined WashU Medicine Marketing & Communications in 2016. She has received three Robert G. Fenley writing awards from the American Association of Medical Colleges: a bronze in 2020 for "Mind’s quality control center found in long-ignored brain area," a silver in 2022 for "Mice with hallucination-like behaviors reveal insight into psychotic illness," and a bronze in 2023 for "Race of people given Alzheimer’s blood tests may affect interpretation of results." Since January of 2024, Tamara has been writing under the name Tamara Schneider.