Buying time: a rationale for examining the use of circadian rhythm and sleep interventions to delay progression of mild cognitive impairment to Alzheimer’s disease

Abstract

As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia’s annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer’s disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Aβ), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD—though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-ε4 is proinflammatory and individuals with this genotype accumulate more Aβ, are at high risk of developing AD, and almost half of all AD patients have at least one ε4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Aβ clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the ε4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia.

Self-Reported Sleep Disturbance Mediates the Relationship Between PTSD and Cognitive Outcome in Blast-Exposed OEF/OIF Veterans

“…81,82 Moreover, sleep disruption has been found to contribute to the onset and accumulation of Alzheimer pathology. 83 Given the elevated risk of dementia associated with PTSD 84,85 as well as with TBI, [86][87][88] consideration of sleep as a mediating factor of long-term cognitive outcomes will be of critical importance.…”

“…81,82 Moreover, sleep disruption has been found to contribute to the onset and accumulation of Alzheimer pathology. 83 Given the elevated risk of dementia associated with PTSD 84,85 as well as with TBI, 86-88 consideration of sleep as a mediating factor of long-term cognitive outcomes will be of critical importance.Our study focused on the associations among PTSD, sleep, and cognition, but other mental health symptoms may also contribute to cognitive outcome. Measures of PTSD and depression were highly correlated in our sample.…”

Sleep Duration in Relation to Cognitive Function among Older Adults: A Systematic Review of Observational Studies

“…Thus, there is growing evidence to support a central role of beta-amyloid accumulation in explaining associations between sleep disturbances and cognitive impairment. Still, other studies implicate increased tau protein, neuroinflammation, neurodegeneration, hypoxia, and vascular changes, as well as decreased synaptic plasticity as mediators of this association, any of which may also interact with beta-amyloid to promote further cognitive decrements [24,88] .…”

New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation

“…Extracellular Aβ is vacated by this mechanism twice as fast as during NREM SWS than during awake periods (Xie et al, 2013). If a causal link exists between the accumulation of Aβ in DMN regions and neurodegeneration in AD, interventions that improve sleep among older adults may ameliorate Aβ burden and slow down the sleep‐related AD onset and progression (Figure 3) (Landry and Liu‐Ambrose, 2014; Lucey and Bateman, 2014; Musiek et al, 2015). …”

“…Proposed effects of melatonin on mechanisms linking circadian clocks, sleep and neurodegeneration in AD (adapted from Landry and Liu‐Ambrose, 2014; Musiek and Holtzman, 2016). Sleep–wake and circadian disruption may precede neurodegeneration and the development of cognitive symptoms.…”