Abstract

Background: Understanding the pathophysiology of Alzheimer's disease (AD) is of fundamental importance for improved diagnosis, monitoring and ultimately, treatment. Objective: A role for the sleep-wake cycle in the pathogenesis of AD has been proposed, but remains to be worked out in detail. Methods: Here we draw together several lines of previous work to outline a ‘hypnic hypothesis' of AD. Results: We propose that altered function of brainstem neurotransmitter pathways associated with sleep, promotes regionally specific disintegration of a cortico-subcortical ‘default mode' brain network that is selectively vulnerable in AD. Conclusion: The formation of a dynamic toxic state within this vulnerable network linked to sleep-wake disruption, would in turn lead to failure of synaptic repair, increased transmission of pathogenic misfolded proteins and a self-amplifying neurodegenerative process. We consider the evidence for this hypnic hypothesis and the implications that follow on from it.