Together these data suggest that glymphatic CSF-ISF exchange, and its role in clearance of tau from the brain, are impaired in this tau Alzheimer’s disease model, and that blocking AQP4 leads to decreased tau clearance, supporting pharmacological targeting of AQP4 for glymphatic modulation in tauopathic dementias such as Alzheimer’s disease. Here, MAPT is linked to early-onset autosomal dominant Alzheimer disease.