AbstractLacking conventional lymphatic system, the central nervous system requires alternative clearance systems, such as the glymphatic system, which promotes clearance of interstitial solutes. Aquaporin-4 water channels (AQP4) are an integral part of this system and related to neuropathologies, such as Alzheimer’s disease (AD). The clearance of Alzheimer’s associated proteins amyloid β and tau is diminished by glymphatic system impairment, due to lack of AQP4. Even though AQP4 mislocalisation (which affects its activity) is a phenotype of AD, it remains a controversial topic, as it is still unclear if it is a phenotype-promoting factor or a consequence of this pathology. This review provides important and updated knowledge about glymphatic system, AQP4 itself, and their link with Alzheimer’s disease. Finally, AQP4 as a therapeutic target is proposed to ameliorate Alzheimer’s Disease and other neuropathologies AQP4-related.