MAPT and Alzheimer disease: Cryo-EM has shown that tau fibrils formed from heparin in vitro are distinct from those so far seen in human disease.13 RNA and heparan sulfate proteoglycans are associated with neurofibrillary tangles of tau in AD,14–16 whilst non-proteinaceous densities in the cryo-EM maps of tau fibrils from AD,5 PiD,6 CTE8 and CBD7 brain tissue suggest the incorporation of an unknown cofactor.17 Ultimately, it remains unknown whether cofactors are a trigger or consequence of tau aggregation in vivo.