Small tau aggregates exhibit disease-specific molecular profiles across tauopathies

Tauopathies are neurodegenerative diseases marked by pathological tau aggregation. While disease-specific folds of insoluble tau filaments have been established, it remains unclear whether the smaller, earlier species also differ across tauopathies. Here, we characterise these small tau aggregates from post-mortem brain of individuals with Alzheimers disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Picks disease, and healthy controls. Using two complementary single-molecule assays, we confirm that small tau aggregates vary in abundance, morphology, and post-translational modifications. AD features specific long, fibrillar-shaped aggregates enriched in phospho-epitopes, while PSP aggregates are shorter, round, and selectively phosphorylated at serine-356, a site we identify as correlating with markers of inflammation and apoptosis. Aggregate properties co-vary with cellular stress signatures and align with disease-specific seeding profiles, suggesting distinct pathological mechanisms. These findings suggest that small tau aggregates are not a shared intermediate, but instead encode disease-specific mechanisms, with potential as both biomarkers and therapeutic targets. Key pointsSmall tau aggregates show disease-specific signatures across tauopathies, differing in abundance, morphology, and post-translational modifications. Tau aggregates in AD show enhanced phosphorylation density and structural heterogeneity, including a distinct population of long fibrillar species detectable in the soluble fraction. Alzheimers disease is characterised by specific long, fibrillar-shaped tau aggregates enriched in disease-relevant phospho-epitopes. PSP features round pSer356-positive aggregates that correlate with apoptotic and inflammatory markers, suggesting a distinct mechanism of toxicity. Isoform-specific biosensor assays reveal divergent seeding behaviour: CBD shows strong 4R seeding, while PSP lacks seeding activity. Features of small aggregates co-vary with distinct patterns of gliosis and cell stress, suggesting disease-specific mechanisms of tau-mediated toxicity.