Objective To explore the key E3 ubiquitin ligases and their expression profile in the pathogenesis of Alzheimer’s disease (AD).Methods Bioinformatics method was used to screen the differential expression genes (DEGs) in the development of AD. The DEGs were analyzed by gene ontology (GO) and protein-protein interaction (PPI) network. Then, the E3 ubiquitin ligases were looked up through The Human Protein Atlas and Alzdata databases to find their histocytological localization in different brain regions. It was verified by qPCR in AD mice brain tissue.Results Ubiquitin-proteasome system (UPS) and ubiquitin conjugating enzyme from Trypanosoma cruzi (UBCc) domains of ubiquitin-conjugating enzyme were ranked top in the biological functions and domains involved in the process of AD; PPI network revealed multiple UPS molecules are the key node proteins; brain tissues specific and highly expressed E3 ubiquitin ligases (MKRN2, NEDD4L, LNX1, RNF41, TRIM36, RNF8 and DTX4) are reduced in AD patients and AD mice.Conclusion These 7 E3 ubiquitin ligases may function as driving factors to participate in the progress of AD, which provides important clues for further searching for new targets for the diagnosis, treatment and in-depth mechanism exploration in AD progression.