Together, these data revealed an intriguing relationship between the extent of neuronal HMGB1 translocation and the severity of microgliosis and neurodegeneration in the presence of APOE4, suggesting that HMGB1 likely plays an important role in the pathogenic mechanism of APOE4-driven gliosis and consequently neurodegeneration in the context of tauopathy. Here, APOE is linked to tauopathy.