P4–021: A hypnic hypothesis of Alzheimer's disease

Abstract

condition. Molecular biological, biochemical and neuroimaging studies have yielded a substantial body of data on the causes and evolution of AD [1][2][3][4][5] , whilst the concept of a vulnerable distributed brain network provides a framework for explaining how molecular events might scale up to a clinical phenotype [6][7][8][9] . It is increasingly clear that AD has a protracted prodromal phase prior to clinical onset during which potentially pathogenic factors could operate and might have cumulative effects [5] .On a biochemical level, synaptic alterations are hypothesised to play a key role in the pathogenesis of many neurodegenerative diseases, including AD [9][10][11] . Such alterations may promote the transfer of pathogenic molecular species (in particular, β-amyloid oligomers) leading to the diffusive spread of misfolded proteins (in particular, hyperphosphorylated tau) throughout a vulnerable, distributed brain network, the so-called 'default mode network' (DMN) that appears to be integral to the operation of the normal resting brain [12][13][14][15][16] . Most accounts of synaptic dysfunction in AD emphasise molecular and biochemical events impacting on synaptic physiology via a loss of structural integrity [11,17] . However, an alternative (and by no means mutually exclusive) possibility is the promotion of synaptic damage by altered patterns of synaptic activity and excitotoxicity [18] . A fundamental example of a pervasive, phasic alteration in synaptic activity is the circadian sleep-wake cycle, which is associated with profound changes in many aspects of cellular and synaptic function [19,20] . Key WordsSleep · Alzheimer's disease · Neurodegeneration · Default mode network 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 neuro transmitter pathways associated with sleep, promotes regio nally 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.

Does sleep disturbance affect the amyloid clearance mechanisms in Alzheimer's disease?

“…There are various theories hypothesizing that sleep disturbances might worsen the AD pathology through increased wakefulness and related excitotoxicity . Moreover, recent studies indicate that altered function of brainstem neurotransmitter pathways secondary to sleep impairment might lead to the impairment of the ‘default mode’ brain network, which is a key pathophysiological mechanism in AD . In recent years, human Aβ metabolism has received considerable critical attention in regards to clarifying the pathophysiological relation between sleep and AD pathogenesis.…”