Although it was previously unclear how APOE4 induces neuroinflammation, we show that APOE4 has a compelling effect of promoting the intraneuronal translocation and release of HMGB1, which is a key pro-neuroinflammatory DAMP in the brain.36,60 Interestingly and importantly, pharmacological inhibition of HMGB1 intracellular translocation and release reduces not only gliosis, but also Tau pathology in APOE4 tauopathy mice. The gene discussed is MAPT; the disease is tauopathy.