Fig. 1.

Schematic of tau pathology in sleep, wake, and circadian brain regions and pathways. The ascending arousal system (blue) leading to cortical arousal is composed of brain regions active in wake (blue circles) or both wake and REM sleep (blue stars). Many of these regions are shown to be affected by abnormal tau pathology in pretangle stages, prior to cortical tau or Aβ pathology (pink outline) or in clinical AD (purple outline), suggesting a role for tau in sleep-wake dysregulation in aging and AD. The hypothalamic VLPO (orange square) sleep generating region inhibits wake active areas of the ascending arousal system (orange dash). However, the VLPO as well as the circadian master clock SCN (brown triangle) have not been shown to have significant tau pathology (no outline) in AD. The REM sleep producing SLD (green), which interacts with the REM-off ventrolateral PAG, and NREM/SWS generating PFZ (light purple) have not yet been studied for the presence of tau pathology (yellow outline) but could play a role in sleep loss seen in AD. Adapted by permission from Macmillan Publishers Ltd: Neuron (Saper et al., 2005).