0.65). pT217 enriched tau had a constrained phosphorylation signature compared to PHF1 enriched tau, but interactors shared significant overlap. The phosphorylation patterns of pT217 enriched tau included lower intensities of phosphorylation at epitopes serine 396 and serine 404 than PHF1 enriched tau, suggesting pT217 tau was at an earlier state of dysregulation. pT217 interacting proteins were most significantly enriched for biological processes involved in protein catabolism, highlighting the CTLH E3 ubiquitin ligase complex as a novel interactor of multiple phosphorylated tau species (5 interacting subunits: WDR26, ARMC8, GID8, RANBP9, MAEA). In APOE e3/e3 cases pT217 significantly interacted with 46 proteins compared to 28 in APOE e4/e4 cases. These interacting proteins were significantly overlapped, with 13 proteins in common (Fishers exact p = 9x10-23). CTLH E3 ubiquitin ligase subunits significantly interacted with phosphorylated tau in both APOE genotypes. pT231 immunoprecipitation failed to sufficiently enrich tau but results are provided in supplementary data. The phosphorylated tau interaction with p62 and the CTLH component WDR26 were validated using co-immunoprecipitation and immunofluorescent microscopy of fixed post-mortem human brain tissue. In conclusion, our results report the interactome of pT217 in human Alzheimers disease brain tissue for the first time and highlight the CTLH complex as a significant novel interactor of multiple types of phosphorylated tau, including those increased early in Alzheimers disease. The mass spectrometric files of this AP-MS experiment are included here. ]]>