Silkworms are an economically important insect.Silkworm pupae are also a nutrient-rich food and can be used as a pharmaceutical intermediate.The N-terminus of Aβ includes 1–15 amino acid residues with a B cell surface antigen that is necessary to produce antibody and prevent the adverse reactions observed in response to the full Aβ42 peptide. In this study, we used silkworm pupae to develop a safer vaccine for Alzheimer’s disease (AD) patients. Aβ15 peptide was fused with the cholera toxin B subunit (CTB) and expressed in silkworm pupae. Then, we tested an oral vaccine with the peptide expressed by silkworm pupae in a transgenic mouse model of AD. The results show that anti-Aβ antibodies were induced, Aβ deposition in the brain decreased, the content of malondialdehyde was lower than in the other group, and memory and cognition of the mice improved. These results suggest that the high-nutrient CTB-Aβ15 silkworm pupa vaccine has a potential clinical application for the prevention of AD.