In the current study, we aimed to gain an in-depth understanding of the relationship between APOE4 and HMGB1 in the setting of tauopathy by (1) evaluating the differential effects of APOE4 and APOE3 on the nucleocytoplasmic translocation and release of HMGB1 protein; (2) elucidating the potential APOE isoform-specific connection between HMGB1 translocation and release, gliosis, and degeneration; and (3) determining the therapeutic efficacy of utilizing HMGB1 inhibitors to mitigate the development of APOE4-driven AD pathologies in a tauopathy mouse model. This evidence concerns the gene APOE and tauopathy.