Recently, concerns have been raised over using a one-size-fits-all approach to AD therapeutic development, and a paradigm shift has been suggested toward developing therapeutics that target specific genetically driven pathogenic mechanisms.80–82 Our study supports the notion that targeting the detrimental effects of APOE4 on HMGB1 intracellular translocation and release could serve as a therapeutic approach toward combating AD pathologies that are strongly driven by APOE4. Here, HMGB1 is linked to Alzheimer disease.