Microglial contributions to the effects of APOE on tau-linked pathologies. APOE ε4 is linked with harmful microglial states that exacerbate tau pathology. Tau-induced microglial reactivity is modulated by the APOE genotype, with ε4 conferring the highest microglial reactivity and ε2 the lowest, whereas microglia in an APOE KO context present even lower reactivity. APOE ε4 is linked to higher tau pathology, neuronal loss, and neuroinflammation, an effect that is exacerbated following depletion of TREM2, a crucial regulator of the microglial response. On the other hand, microglial depletion has an opposite effect and dampens the influence of APOE ε4 on tau pathology. In the context of tau pathology, the loss of microglial APOE has opposing effects according to the specific isoform. Loss of microglial apoE3 leads to a reduced number of reactive microglia, resulting in enhanced levels of p-tau and subsequent neuronal loss. In contrast, removal of microglial apoE4 enhances the level of reactive microglia, reducing the levels of p-tau and neuronal loss, thus demonstrating the negative influence of apoE4 on tau pathology. https://BioRender.com/u31n304.