Alzheimer's disease is characterized by extracellular deposits of amyloid β peptide in the brain. Increasing evidence suggests that amyloid β peptide injures neurons both directly and indirectly by triggering neurotoxic innate immune responses. Myeloid differentiation factor 88 is the key signalling molecule downstream to most innate immune receptors crucial in inflammatory activation. For this reason, we investigated the effects of myeloid differentiation factor 88-deficient bone marrow cells on Alzheimer's disease-related symptoms and pathology by establishing bone marrow chimeric amyloid β peptide precursor transgenic mice, in which bone marrow cells differentiate into microglia and are recruited to amyloid β peptide deposits. We observed that myeloid differentiation factor 88-deficient bone marrow reconstruction reduced both inflammatory activation and amyloid β peptide burden in the brain. In addition, synaptophysin, a marker of neuronal integrity, was preserved and the expression of neuronal plasticity-related genes, ARC and NMDA-R1, was increased. Thus, myeloid differentiation factor 88-deficient microglia significantly improved the cognitive function of amyloid β peptide precursor protein transgenic mice. Myeloid differentiation factor 88-deficiency enhanced amyloid β peptide phagocytosis by microglia/macrophages and blunted toxic inflammatory activation. Both the expression of amyloid β peptide precursor protein and amyloid β peptide degrading enzymes and also the efflux of amyloid β peptide from brain parenchyma were unaffected by myeloid differentiation factor 88-deficient microglia. By contrast, the activity of β-secretase was increased. β-Secretase is expressed primarily in neurons, with relatively little expression in astrocytes and microglia. Therefore, microglial replenishment with myeloid differentiation factor 88-deficient bone marrow cells might improve cognitive functions in Alzheimer's disease mouse models by enhancing amyloid β peptide phagocytosis and reducing inflammatory activation. These results could offer a new therapeutic option that might delay the progression of Alzheimer's disease.