MTBR-Tau243 in Cerebrospinal Fluid Revealed as a Specific Alzheimer Disease Biomarker
A recent analysis showed a form of tau that could serve as a biomarker to track and explore whether investigational tau-based drugs are effective against Alzheimer disease.
Randall J. Bateman, MD
Newly published in Nature Medicine, an extended analysis revealed a specific form of tau, known as microtubule binding region (MTBR)-tau243, in cerebrospinal fluid (CSF) of patients with Alzheimer disease (AD), with potential to track damaging tau and cognitive decline. Investigators concluded that a test based on this biomarker could speed up treatment development and explore whether the experimental therapies can change the course of the disease progression.1,2
Among 667 patients at various stages of AD in Sweden and the U.S., MTBR-tau243 was most significantly associated with tau-PET and cognition compared with the lowest association shown with amyloid-PET. When used in combination with p-tau205, this specific tau demonstrated most of the total variance in tau-PET burden (.58 ≤ R2 ≤ .75) and the performance in predicting cognitive measures (.34 ≤ R2 ≤ .48) approached that of tau-PET (.44 ≤ R2 ≤ .52). Notably, the MTBR-tau243 levels increased longitudinally with the insoluble tau aggregates compared with the CSF p-tau species.
“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,” cosenior author Randall J. Bateman, MD, the Charles F. and Joanne Knight distinguished professor of neurology at Washington University said in a statement.1 “These findings will help accelerate drug development for patients with symptoms of AD. We are also working on developing these biomarkers as a clinical test to stage individual patients and improve patient care.”
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In this new study, researchers at Washington University School of Medicine in St. Louis and Lund University in Lund, Sweden, did an extended analysis from a previous study3 involving a larger number of patients to compare MTBR-tau243 with other tau biomarkers. They analyzed data from patients who volunteered for AD research studies through the Biomarkers For Identifying Neurodegenerative Disorders Early and Reliably study (n = 448) in southern Sweden or the Knight Alzheimer Disease Research Center (n = 219) in St. Louis. The research group included healthy patients as well as patients at all stages of the disease, with an average age of 71 years old. The investigators compared cognitive function with levels of various forms of tau in the CSF and with levels of amyloid and tau, as measured by PET scans.
“To accurately diagnose AD in patients with cognitive symptoms, we need biomarker-based evidence of both amyloid beta plaques and tau tangle pathology,” Hansson said in a statement.1 “With this new biomarker, representing tau pathology, we can do this using a single CSF sample. This has the potential to clearly improve the diagnostic as well as prognostic work-up of Alzheimer worldwide. We hope that we soon can do the same using a simple blood test.”
The authors had the ability to use the 2 forms of tau in the CSF, phosphorylated tau and MTBR-tau243, in combination to predict cognitive function almost as well as using the tau-PET. “A combination of phosphorylated tau and MTBR-tau243 in the CSF reveals not only whether an individual has AD but identifies the stage of illness – from presymptomatic disease to full-blown dementia,” Horie said in a statement.1
The researchers could also track disease progression and indicate the effect of interventions, such as experimental antitau therapeutics on the disease trajectory, when taking repeated samples of CSF. “In late stages of AD, the effectiveness of antiamyloid therapies may weaken because amyloid is no longer playing a major role in driving the disease,” Horie said in a statement.1 “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.”
