Background: Most Alzheimer’s disease (AD) cases arise sporadically and may involve innate immune activation of microglial expressed Toll-like receptors regulated through the myeloid differentiation protein 88 (MyD88) pathway. Objective: It was the aim of this study to test the innate immune involvement in AD pathology. Methods: We mated APPsw/PS1ΔE9 mice with MyD88-deficient mice. Results: Progeny mice had similar levels of soluble amyloid-β peptides, amyloid plaque density and neuroimmune staining patterns. However, double-transgenic mice did show a significantly reduced life expectancy. Conclusion: Our findings indicate that impaired innate immune responses may play a role in AD pathology.