MAPT and Alzheimer disease: The data presented here support the hypothesis and demonstrate (i) major inter-individual structural diversity of MTBDs in tau conformers isolated from AD with different progression rates, particularly in the fourth repeat (R4) tau domain, (ii) a significant role of the structural organization and exposure of the R4 domain within the MTBDs in the replication and propagation of tau conformers, and (iii) a striking correlation between structural exposure of the first repeat (R1) domain and toxicity in neuronal cultures.