The cognitive decline in Alzheimer's disease (AD) is associated with elevated brain levels of amyloid β-protein (Aβ), particularly Aβ1-42. Angiotensin-converting enzyme (ACE) can enzymatically degrade Aβ1-42 and its overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE10/10 mice, which over express ACE in myelomonocytic cells, with the double-transgenic APPSWE/PS1ΔE9 mouse model of AD (AD+). At 7 months, soluble Aβ1-42 was reduced by 44% (136 vs 245 pg/mg) and Aβ1-40 was reduced by 32% (21 vs 31 pg/mg). Plaque burden was reduced by as much as 79% (13 vs 62 103mm2) and insoluble Aβ1-42 by 64% (189 vs 521 pg/mg). There was also a substantial reduction in astrogliosis (49-57% at 7 months, 50% at 13 months). AD+ACE10/10 mice demonstrated less overall brain infiltrating cells, consistent with less AD pathology, though ACE-overexpressing monocytes and macrophages were increasingly abundant surrounding and engulfing Aβ plaque. At 11 and 12 months, AD+ACE10/WT and AD+ACE10/10 mice were virtually equivalent to non-AD mice in cognitive ability as assessed by maze-based behavioral tests. This study shows that an enhanced immune response, coupled with increased myelomonocytic cell expression of ACE, resulted in essentially complete prevention of the cognitive decline observed in a murine model of AD.