Recently, we showed that neuronal APOE4 is a strong driver of Tau pathology, gliosis, and hippocampal degeneration in this PS19 tauopathy mouse model and that the selective removal of APOE4 from neurons protects against the development of these pathologies.23 In this study, we demonstrate that removing neuronal APOE4 significantly reduces the extent of neuronal HMGB1 translocation and release into the hippocampal ISF. The gene discussed is HMGB1; the disease is tauopathy.