Nanoscopic tau aggregates are not shared intermediates but disease-specific entities across tauopathies

• Small tau aggregates are disease-specific species rather than shared intermediates • Alzheimer’s disease features distinct long, hyperphosphorylated fibrillar aggregates • PSP is marked by pSer356-positive aggregates linked to inflammation and apoptotic stress • Aggregate features align with divergent seeding profiles and cellular stress responses Small tau aggregates are disease-specific species rather than shared intermediates Alzheimer’s disease features distinct long, hyperphosphorylated fibrillar aggregates PSP is marked by pSer356-positive aggregates linked to inflammation and apoptotic stress Aggregate features align with divergent seeding profiles and cellular stress responses 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 characterize these small tau aggregates from postmortem brain of individuals with Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration, Pick’s 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.