Brain rhythm attractor breakdown in Alzheimer's disease: Functional and pathologic implications

Abstract

This perspective binds emerging evidence on the bidirectional relationship between Alzheimer’s disease (AD) and sleep disorders through a model of brain rhythm attractor breakdown. This approach explains behavioral-cognitive changes in AD across the sleep-wake cycle and supports a causal association between early brainstem tau pathology and subsequent cortical amyloid-β accumulation. Specifically, early tau dysregulation within brainstem-hypothalamic nuclei leads to breakdown of sleep-wake attractor networks, with patients displaying an attenuated range of behavioral and electrophysiological activity patterns, a “twilight zone” of constant activity between deep rest and full alertness. This constant cortical activity promotes activity-dependent amyloid-β accumulation in brain areas that modulate their activity across sleep-wake states, especially the medial prefrontal cortex (mPFC). Additionally, the accompanying breakdown of hippocampal-mPFC interplay across sleep stages could explain deficient memory consolidation through dysregulation of synaptic plasticity. Clinical implications include the potential therapeutic benefit of attractor consolidation (e.g., slow-wave sleep enhancers) in delaying AD progression.

Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers

“…Overall, the above findings support for the first time the consideration of trazodone for clinical use, not only toward improving quality of life in older adults by increasing sleep duration [10], but also as an intervention against cognitive decline. The findings are also in keeping with the therapeutic concept of consolidating brain rhythms of sleep and wakefulness toward delaying neurodegeneration and optimizing synaptic plasticity [16]. On this basis, sleep consolidation, as defined by integrity of sleep continuity and architecture, can be directly achieved through medications that consolidate sleep rhythms [26], as well as indirectly by consolidating rhythms of wakefulness that in turn allow deeper rhythms in subsequent sleep [27, 28].…”

“…Trazodone group comparative delay in cognitive decline persisted when accounting for concomitant use of medications that modulate brain rhythms, such as stimulants and sedatives, which may signify trazodone’s contribution to sleep-wake and ultradian rhythm consolidation toward delayed cognitive decline [16]. However, when specifically accounting for ChEi use, trazodone users did not significantly benefit in delayed cognitive decline compared to non-users.…”

The rate of transient beta frequency events predicts behavior across tasks and species

“…Modulations in beta power correlate with perceptual and motor demands ( Bauer et al, 2006 ; Bressler and Richter, 2015 ; Engel and Fries, 2010 ; Haegens et al, 2011 ; Jones et al, 2010 ; Miller et al, 2012 ; Neuper and Pfurtscheller, 2001 ; Sacchet et al, 2015 ; Siegel et al, 2008 ; van Ede et al, 2011 ) and abnormalities in beta are a biomarker for neuropathology (e.g. in Parkinson’s disease, Alzheimer’s disease and Autism Spectrum Disorder [ Karageorgiou and Vossel, 2017 ; Khan et al, 2015 ; Little and Brown, 2014 ]). Yet, how and why beta impacts function is debated.…”

The rate of transient beta frequency events predicts impaired function across tasks and species

“…Modulations in beta power correlate with perceptual and motor demands ((1-10)) and abnormalities are used as a biomarker of neuropathology (e.g. Parkinson's disease, Alzheimer's disease, Autism Spectrum Disorder (11)(12)(13)). Yet, how and why beta impacts function is yet unknown.…”