Targeting the apoE–tau interplay for therapeutic interventions. Given the evidence of the effects APOE has on tau pathology and tau-mediated neurodegeneration, a series of therapeutic approaches targeting tau through apoE have been proposed. Specific removal of astrocytic or microglial apoE has proven beneficial with regard to tau-mediated neuronal loss. The reduction of apoE levels through ASOs or LDLR overexpression has shown preclinical promise in reducing tau pathology. Anti-apoE antibodies targeting nonlipidated amyloid-bound apoE reduce Aβ-mediated tau seeding and spreading. To mitigate the risks of apoE depletion, apoE mimetic antibodies that compete particularly with apoE4 for binding at receptors are a potential approach. Finally, molecules correcting the structure of apoE4 to that of apoE2 or apoE3 have been shown to recover the functionality of apoE.