APOE is the major genetic risk factor for sporadic Alzheimer's disease (AD). Although APOE is known to promote Aβ pathology, recent data also support an effect of APOE polymorphism on phosphorylated Tau (pTau) pathology. To elucidate these potential effects, the pTau interactome was analyzed across APOE genotypes in the frontal cortex of 10 advanced AD cases (n = 5 APOE and n = 5 APOE), using a combination of anti-pTau pS396/pS404 (PHF1) immunoprecipitation (IP) and mass spectrometry (MS). This proteomic approach was complemented by an analysis of anti-pTau PHF1 and anti-Aβ 4G8 immunohistochemistry, performed in the frontal cortex of 21 advanced AD cases (n = 11 APOE and n = 10 APOE). Our dataset includes 1130 and 1330 proteins enriched in IP samples from APOE and APOE groups (fold change ≥ 1.50, IP vs IP). We identified 80 and 68 proteins as probable pTau interactors in APOE and APOE groups, respectively (SAINT score ≥ 0.80; false discovery rate (FDR) ≤ 5%). A total of 47/80 proteins were identified as more likely to interact with pTau in APOE vs APOE cases. Functional enrichment analyses showed that they were significantly associated with the nucleoplasm compartment and involved in RNA processing. In contrast, 35/68 proteins were identified as more likely to interact with pTau in APOE vs APOE cases. They were significantly associated with the synaptic compartment and involved in cellular transport. A characterization of Tau pathology in the frontal cortex showed a higher density of plaque-associated neuritic crowns, made of dystrophic axons and synapses, in APOE carriers. Cerebral amyloid angiopathy was more frequent and severe in APOE cases. Our study supports an influence of APOE genotype on pTau-subcellular location in AD. These results suggest a facilitation of pTau progression to Aβ-affected brain regions in APOE carriers, paving the way to the identification of new therapeutic targets.