A Hypnic Hypothesis of Alzheimer's Disease

Camilla N. Clark, Jason D. Warren
2013 Neurodegenerative Diseases  
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
more » ... ave 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 [9-11] . 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] . 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.
doi:10.1159/000350060 pmid:23635607 pmcid:PMC3884167 fatcat:qktxxxy4qzhybet5xf4sbxltv4