EVs are bilipid spheres known for their role in cellular communication through transport of proteins, lipids, RNA and more. In the brain, EVs are directly released in the interstitial fluid surrounding neural cells and hence entitled brain-derived EVs (BD-EVs). Human BD-EVs of AD patients contain seed-competent tau. Further, we demonstrated a different tau seeding capacity of AD, PSP and PiD patients derived EVs. This reflects a heterogenous contribution of BD-EVs to tau seeding among tauopathies, with AD BD-EVs showing the highest seeding capacity. Here, we aim to identify and compare the tau proteoforms found within EVs of tauopathies to assess if this tau content lays at the base of the heterogeneity observed for EVs seeding among tauopathies. A tau immunoprecipitation followed by mass spectrometry analysis (tau IP-MS), performed on BD-EVs from non-demented controls or patients affected with different tauopathies, revealed detection of 22 tryptic tau peptides with two MTBR tryptic peptides enriched only in AD BD-EVs. Among them, the well-known pro-aggregative hexapeptide PHF6 (VQIVYK) was found. Importantly, we demonstrated that PHF6-containing tau proteins are strongly implied in the seeding capacity of AD BD-EVs. From this, we conclude that the PHF6 is a driver for the higher EVs-mediated tau propagation in AD patients, revealing an interesting therapeutic target to prevent tau pathology spreading.