TAR DNA/RNA-binding domain protein 43 (TDP-43) has become one of the pathogenic factors of many neurodegenerative diseases, such as Alzheimer's disease (AD). Clearance of abnormal accumulation of TDP-43 might be the potential treatment target in AD patients. Ubiquitin-proteasome system (UPS) is one of the main ways of protein clearance. UPS dysfunction plays an important role in the pathogenesis and progression of AD. This review focuses on the roles of TDP-43 and UPS in the pathogenesis of AD, as well as the research progress of UPS mediated clearance TDP-43 in the treatment of AD.