In addition, we initiated long-term treatment with HMGB1 inhibitors when the tauopathy mice were 6.5 months of age, which is before they develop severe gliosis or degeneration phenotypes.50 When considering the treatment of human APOE4 AD patients with HMGB1 inhibitors or specific anti-HMGB1 antibodies, it will be important to determine at which stage in the disease the inhibitors will be most effective. Here, APOE is linked to Alzheimer disease.