Objective To establish a germ-free mouse strain to provide a new animal model for studies on therelationship between gut flora and Alzheimer’s disease and the changes of amyloid plaques in the brain, by establishing a APPswe / PS1ΔE9 (PAP) transgenic mouse model using a cesarean section decontamination technique. Methods Cesareansection was performed on pregnant PAP mice to obtain pups under a SPF barrier environment, and the pups were thentransferred to female germ-free ICR mice that served as foster mothers. Survival rates of the pups were calculated at 7 daysof age and after weaning. Pathogens were tested each month according to the national standards. The newborn PAP micewere genotyped by polymerase chain reaction (PCR). The deposition of Aβ plaques in brain tissue were observed usingimmunohistochemical staining. Result 12 cesarean sections were performed on pregnant PAP mice, and a total of 63 pupswere collected and transferred to a foster mother. The survival rate of pups after cesarean section and weaning was 95. 45%(63/66) and 95. 24% (60/63), respectively. Pathogens were tested after decontamination, and all the pups werepathogen-negative, thus met the requirement of germ-free mice. The deposition of Aβ plaques was lower in the germ-freePAP mice than in SPF mice of the same age. Conclusions A germ-free PAP mouse model is established by cesareansection and foster mother technique. This new animal model can be used for studies on the relationship between gut flora and Alzheimer’s disease and the changes of amyloid plaques in the brain tissue.