APOE and Alzheimer disease: In addition to Clu, Gfap, Igfbp5, and Prdx6, rh Bri2 BRICHOS R221E treatment also affected the expression of Trem2 and ApoE. It is interesting to note that activation of the TREM2-ApoE pathway was found to shift microglia towards a phagocytic state with activity against neuritic amyloid plaques and apoptotic neurons [78], and that the ApoE3 isoform was more efficient in increasing TREM2 expression and in mounting an Aβ-induced microglial response compared to the ApoE4 isoform, which is associated with increased risk of developing AD [79].