The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of beta-amyloid (A beta) that accumulates in Alzheimer's disease (AD). Furthermore, chronic sleep deprivation (SD) increases A beta plaques. However, tau, not Ab, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased similar to 90% during normal wakefulness versus sleep and similar to 100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF A beta and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.