Circulating monocytoid cells have the ability to infiltrate nervous tissue, differentiate into microglia, and clear amyloid-β (Aβ) from the brain of mouse models of Alzheimer's disease. Interaction between the chemokine CCL2 and its CC chemokine receptor 2 (CCR2) plays a critical role in the recruitment of inflammatory monocytes into the injured/diseased brain. Here, we show that CCR2 deficiency aggravates mnesic deficits and amyloid pathology in transgenic mice expressing the chimeric mouse/human β-amyloid precursor protein and presenilin 1 (APP_Swe/PS1). Indeed, memory impairment was accelerated and enhanced in APP_Swe/PS1/CCR2^−/− mice. Apparition of cognitive decline occurred earlier (i.e., at 3 months of age before plaque formation) and correlated with intracellular accumulation of soluble oligomeric forms of Aβ. Memory deficits worsened with age and were aggravated in APP_Swe/PS1/CCR2^−/− mice compared with their respective control groups. Soluble Aβ assemblies increased significantly in APP_Swe/PS1 mice in a context of CCR2 deficiency, whereas the plaque load remained relatively similar in the brain of aging APP_Swe/PS1 and APP_Swe/PS1/CCR2^−/− mice. However, CCR2 deficiency stimulated the expression of TGF-β1, TGF-β receptors, and CX₃CR1 transcripts in plaque-associated microglia, a pattern that is characteristic of an antiinflammatory subset of myeloid cells. A decreased expression of CCR2 could play a potential role in the etiology of Alzheimer's disease, a neurodegenerative pathology that could be treated by a genetic upregulation of the transgene in monocytoid cells.