In tandem with seeding and propagation rates determined in vitro and in neuronal cultures, the data demonstrated (i) major inter-individual structural diversity of MTBDs in tau conformers isolated from AD with different progression rates, (ii) striking variability in the fourth repeat (R4) tau domain, and (iii) a significant role of the structural organization and exposure of the R4 domain within the MTBDs in the replication and propagation of tau conformers (Fig 6). This evidence concerns the gene MAPT and Alzheimer disease.