As HMGB1 binds to and activates RAGE and TLR4, culminating in nuclear translocation of NFκBp65 contributing to complex proinflammatory signaling (Maroso et al., 2010; Volz et al., 2010; Zurolo et al., 2011; Tang et al., 2012; Mayfield et al., 2013; Yang et al., 2020; Macht et al., 2023), HMGB1 is poised to play a crucial role as an immunoregulator underlying persistent AIE-induced proinflammatory signaling and acceleration of AD-associated neuropathology. This evidence concerns the gene TLR4 and Alzheimer disease.