MAPT and Alzheimer disease: Possible mechanistic pathways linking sleep as a risk factor for AD include the diurnal nature of the sleep-wake cycle and its effects on extracellular metabolism of Aβ and tau in the CSF and in brain interstitial fluid (ISF) as these fluctuate diurnally, with soluble Aβ levels higher during wakefulness, and lower during sleep (Kang et al., 2009).