From clinical phenotypes to molecular stratification: early differential diagnosis of four-repeat tauopathies

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are primary tauopathies defined by aggregation of four-repeat (4R) tau, yet early in vivo diagnosis remains limited by the dissociation between clinical phenotype and molecular pathology. Clinical presentations are heterogeneous, evolve over time, and frequently overlap with Alzheimer's disease, synucleinopathies, and mixed pathologies, particularly in corticobasal syndrome. As a result, clinical criteria provide structured phenotypic classification but have constrained specificity in early disease. This review synthesizes current evidence relevant to early diagnostic stratification in 4R tauopathies, integrating clinical criteria, supportive biomarkers of neurodegeneration, and emerging tau-directed molecular tools. The probabilistic value and limitations of contemporary criteria frameworks are discussed alongside the role of structural and functional imaging, dopaminergic imaging, and fluid markers as indicators of disease intensity and progression rather than molecular specificity. Advances in tau positron emission tomography and tau seed amplification assays are reviewed as biologically grounded approaches that directly interrogate aggregated and seed-competent tau species, with growing evidence for their potential contribution to individual-level stratification. Collectively, the literature supports a layered diagnostic approach in which clinical phenotype, supportive biomarkers, and tau-directed molecular measures are integrated to refine attribution of 4R tau pathology in vivo, a prerequisite for mechanism-based therapeutic development.