One potential mechanism by which amyloid may be more efficiently removed in the human disease than in the mouse models is through microglial phagocytosis. Resident microglia in transgenic mouse models localize to tissue surrounding plaques but show little evidence of amyloid engulfment [37–40]. In contrast, microglia surrounding amyloid plaques in human brain show a much higher state of activation with greater expression of complement receptor [40]. Thus, the role of microglia in amyloid metabolism is minor in transgenic models compared to the human condition. Somewhat paradoxically, several studies further demonstrate that treatment with anti-inflammatory drugs to reduce microglial activation actually lowers amyloid load in APP transgenic mice, suggesting a role for mouse microglia in the formation and maintenance of amyloid aggregates [41–43]. However, this outcome may be alternatively explained by direct effects of many anti-inflammatory drugs on γ-secretase cleavage [44–47]. Nonetheless, the role of microglia in both the human condition and the mouse models is poorly understood, and differences in microglial reactivity between the two could lead to significantly faster amyloid clearance in the brains of patients with AD than we observe in the tet-off APP mice.