This suggests that PAM4 possesses intrinsic structural propensities that influence the organisation of the tauRD into amyloid fibrils that favour the polymorphs observed in disease-related tau aggregates ex vivo, particularly Alzheimer’s disease (AD) (3R + 4R), Corticocal Basal Degeneration (CBD) (4R) and Progressive Supranuclear Palsy (PSP) (4R) polymorphs, a notion further supported by a breakdown of residue energetic contributions in tau fibril cores. Here, MAPT is linked to progressive supranuclear palsy.