This project aims to improve how different forms of abnormal tau are identified across Alzheimer’s disease and related neurodegenerative disorders. Although tau buildup is a shared feature of many brain diseases, the exact structure of tau aggregates can vary widely. Dr. Diamond’s team has shown that many patients’ brains contain multiple distinct tau “strains,” rather than a single uniform form, which may help explain why tau-targeted therapies have had limited success.
To address this challenge, the team developed a new method called alanine scanning, which allows tau structures to be compared more efficiently than traditional imaging approaches. Using this technique, they are uncovering far greater tau complexity than previously recognized, including mixed tau patterns associated with different diseases and entirely new tau structures not described before. These findings suggest that future treatments will need to account for this hidden diversity.
The project has two aims. First, the team is refining alanine scanning to reliably identify complex or unusual tau strain mixtures in human brain samples, with follow-up imaging used to confirm newly predicted structures. Second, they are testing whether commonly used mouse and cell models faithfully reproduce human tau strains by introducing tau from different diseases and analyzing how it spreads in these systems.
By the end of the first year, the team analyzed 48 tauopathy cases and found that mixed tau strains are far more common than expected. Some cases showed Alzheimer’s-type tau alongside other disease signatures, while others contained entirely new tau forms. Early high-resolution imaging has confirmed multiple tau structures within single brains, and parallel studies in animal models are underway. Together, this work is reshaping how tau pathology is understood and is laying important groundwork for more precise diagnostics and better-aligned models to support future tau-targeted therapies.
