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 blood 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.
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.