The Use of a Rapid Biosensor Assay Identifies Co-pathology and Atypical Patterns in Tauopathies
Nil Saez Calveras1, Nabil Morgan2, Jaime Vaquer-Alicea2, Alissa Nana Li3, Sarah Kaufman5, William Seeley4, Marc Diamond6
1Neurology, UT Southwestern Medical Center, 2UT Southwestern Medical Center, 3Pathology, University of California San Francisco, 4University of California San Francisco, 5UCSF, 6University of Texas, Southwestern Medical Center
Objective:

Develop a rapid, cell-based biosensor assay that classifies tauopathies based on how tau alanine point mutants incorporate into seeded aggregates.

 

Background:

Cryogenic electron microscopy (cryo-EM) has enabled a structure-based classification of tauopathies, but it is slow, resource-intensive, requires substantial tissue, and is not available for routine neuropathological use. We sought a practical alternative that infers fold-specific features from tauopathy material with fewer resources and material.

 

Design/Methods:

We engineered six alanine substitutions within the tau repeat domain and expressed each variant in tau biosensor cells. Brain-derived seeds from a library of 50 well-characterized tauopathy cases were used to induce aggregation in the biosensors. For each case, we quantified the incorporation of each mutant into seeded aggregates and used these data to distinguish strains associated with distinct tauopathies. We named this system the Tau Multiplex.

Results:

The Tau Multiplex assay correctly predicted the primary neuropathologic diagnosis for all tested cases and revealed heterogeneity often missed by standard approaches. Overall, 20% of samples showed the presence of co-dominant folds or atypical signatures that did not map to known entities. Notably, 43% of Pick’s disease cases exhibited an additional 4R pattern alongside the expected 3R profile, and 21% of Progressive Supranuclear Palsy cases displayed a distinct 4R signature relative to the canonical pattern. These findings indicate that multiple tau strains can coexist within a single patient and their relative abundance varies across diseases.

 

Conclusions:

The Tau Multiplex is a fast and structure-based system that can complement routine neuropathology. By detecting mixed and atypical strain patterns, it refines diagnostic precision and better reflects the biological diversity of tau aggregates. This approach is well suited to routine practice and larger-scale studies. Looking ahead, the assay could be adapted for the development of in vivo, strain-specific diagnostic tools in biofluids and to support patient classification in clinical trials targeting tau pathology.

10.1212/WNL.0000000000216223
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