Editing Sleep disorder (section)

=== Sleep disturbances and Alzheimer's disease ===
Sleep disturbances have also been observed in [[Alzheimer's disease]] (AD), affecting about 45% of its population.<ref name=":7" /><ref name=":9" /> When based on caregiver reports, this percentage increases to about 70%.<ref name=":13" /> As in the PD population, insomnia and [[hypersomnia]] are frequently recognized in AD patients. These disturbances have been associated with the accumulation of [[Amyloid beta|beta-amyloid]], [[circadian rhythm sleep disorder]]s (CRSD), and [[melatonin]] alteration.<ref name=":7" /><ref name=":9" /> Additionally, changes in [[Sleep|sleep architecture]] are observed in AD.<ref name=":7" /><ref name=":9" /><ref name=":11" /> Although sleep architecture seems to naturally change with age, its development appears aggravated in AD patients. Slow-wave sleep (SWS) potentially decreases (and is sometimes absent), spindles and the length of time spent in REM sleep are also reduced, while its latency increases.<ref name=":13" /> Poor sleep onset in AD has been associated with dream-related hallucinations, increased restlessness, wandering, and agitation related to [[sundowning]]—a typical chronobiological phenomenon in the disease.<ref name=":9" /><ref name=":13" />

In Alzheimer's disease, in addition to cognitive decline and memory impairment, there are also significant sleep disturbances with modified sleep architecture.<ref name=":15">{{cite journal |vauthors=Mander BA, Winer JR, Jagust WJ, Walker MP |date=August 2016 |title=Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease? |journal=Trends in Neurosciences |volume=39 |issue=8 |pages=552–566 |doi=10.1016/j.tins.2016.05.002 |pmc=4967375 |pmid=27325209}}</ref><ref name=":14">{{cite journal |vauthors=Kent BA, Mistlberger RE |date=April 2017 |title=Sleep and hippocampal neurogenesis: Implications for Alzheimer's disease |journal=Frontiers in Neuroendocrinology |volume=45 |pages=35–52 |doi=10.1016/j.yfrne.2017.02.004 |pmid=28249715 |s2cid=39928206}}</ref> These disturbances may consist of sleep fragmentation, reduced sleep duration, insomnia, increased daytime napping, decreased quantity of some sleep stages, and a growing resemblance between some sleep stages (N1 and N2).<ref name=":14" /> More than 65% of people with Alzheimer's disease experience this type of sleep disturbance.<ref name=":14" />

One factor that could explain this change in sleep architecture is a disruption in the circadian rhythm, which regulates sleep.<ref name=":14" /> This disruption can lead to sleep disturbances.<ref name=":14" /> Some studies show that people with Alzheimer's disease have a delayed circadian rhythm, whereas in normal aging, an advanced circadian rhythm is present.<ref name=":14" /><ref>{{cite journal | vauthors = Tranah GJ, Blackwell T, Stone KL, Ancoli-Israel S, Paudel ML, Ensrud KE, Cauley JA, Redline S, Hillier TA, Cummings SR, Yaffe K | display-authors = 6 | title = Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women | journal = Annals of Neurology | volume = 70 | issue = 5 | pages = 722–732 | date = November 2011 | pmid = 22162057 | pmc = 3244839 | doi = 10.1002/ana.22468 }}</ref>

In addition to these psychological symptoms, there are two main neurological symptoms of Alzheimer's disease.<ref name=":15" /><ref name=":14" /> The first is the accumulation of beta-amyloid waste, forming aggregate "plaques".<ref name=":14" /><ref name=":15" /> The second is the accumulation of tau protein.<ref name=":14" /><ref name=":15" />

It has been shown that the sleep-wake cycle influences the beta-amyloid burden, a central component found in Alzheimer's disease (AD).<ref name=":14" /><ref name=":15" /> As individuals awaken, the production of beta-amyloid protein becomes more consistent compared to its production during sleep.<ref name=":14" /><ref name=":15" /><ref name=":16">{{cite journal |display-authors=6 |vauthors=Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M |date=October 2013 |title=Sleep drives metabolite clearance from the adult brain |journal=Science |volume=342 |issue=6156 |pages=373–377 |bibcode=2013Sci...342..373X |doi=10.1126/science.1241224 |pmc=3880190 |pmid=24136970}}</ref> This phenomenon can be explained by two factors. First, metabolic activity is higher during waking hours, resulting in greater secretion of beta-amyloid protein.<ref name=":14" /><ref name=":15" /> Second, oxidative stress increases during waking hours, which leads to greater beta-amyloid production.<ref name=":14" /><ref name=":15" />

On the other hand, it is during sleep that beta-amyloid residues are degraded to prevent plaque formation.<ref name=":14" /><ref name=":15" /><ref name=":16" /> The glymphatic system is responsible for this through the phenomenon of glymphatic clearance.<ref name=":14" /><ref name=":15" /><ref name=":16" /> Thus, during wakefulness, the beta-amyloid burden is greater because metabolic activity and oxidative stress are higher, and there is no protein degradation by glymphatic clearance. During sleep, the burden is reduced as there is less metabolic activity and oxidative stress, in addition to the glymphatic clearance that occurs.<ref name=":15" /><ref name=":14" />

Glymphatic clearance occurs during NREM SWS sleep,<ref name=":14" /><ref name=":15" /><ref name=":16" /> a stage that decreases with normal aging,<ref name=":15" /> leading to reduced glymphatic clearance and increased beta-amyloid burden, which forms plaques.<ref name=":16" /><ref name=":14" /><ref name=":15" /> Therefore, sleep disturbances in individuals with Alzheimer's disease will amplify this phenomenon.

The decrease in the quantity and quality of NREM SWS, along with sleep disturbances, will therefore increase the AB plaques.<ref name=":14" /><ref name=":15" /> This initially occurs in the hippocampus, a brain structure integral to long-term memory formation.<ref name=":14" /><ref name=":15" /> As hippocampus cell death occurs, it contributes to the diminished memory performance and cognitive decline found in AD.<ref name=":14" />

Although the causal relationship is unclear, the development of AD correlates with the onset of prominent sleep disorders.<ref name=":14" /> Similarly, sleep disorders exacerbate disease progression, forming a positive feedback loop.<ref name=":14" /> As a result, sleep disturbances are not only a symptom of AD; the relationship between sleep disturbances and AD is bidirectional.<ref name=":15" />

At the same time, it has been shown that memory consolidation in long-term memory, which depends on the hippocampus, occurs during NREM sleep.<ref name=":14" /><ref name=":17">{{cite journal |vauthors=Diekelmann S, Born J |date=February 2010 |title=The memory function of sleep |journal=Nature Reviews. Neuroscience |volume=11 |issue=2 |pages=114–126 |doi=10.1038/nrn2762 |pmid=20046194 |s2cid=1851910}}</ref> This indicates that a decrease in NREM sleep will result in less consolidation, leading to poorer memory performance in hippocampal-dependent long-term memory.<ref name=":14" /><ref name=":17" /> This drop in performance is one of the central symptoms of AD.<ref name=":14" />

Recent studies have also linked sleep disturbances, neurogenesis, and AD.<ref name=":14" /> The subgranular zone and subventricular zone continue to produce new neurons in adult brains.<ref name=":14" /><ref name=":18">{{cite journal |vauthors=Meerlo P, Mistlberger RE, Jacobs BL, Heller HC, McGinty D |date=June 2009 |title=New neurons in the adult brain: the role of sleep and consequences of sleep loss |journal=Sleep Medicine Reviews |volume=13 |issue=3 |pages=187–194 |doi=10.1016/j.smrv.2008.07.004 |pmc=2771197 |pmid=18848476}}</ref> These new cells are then incorporated into neuronal circuits in the subgranular zone, which is found in the hippocampus.<ref name=":14" /><ref name=":18" /> These new cells contribute to learning and memory, playing an essential role in hippocampal-dependent memory.<ref name=":14" />

However, recent studies have shown that several factors can interrupt neurogenesis,<ref name=":14" /> including stress and prolonged sleep deprivation (more than one day).<ref name=":14" /> The sleep disturbances encountered in AD could therefore suppress neurogenesis and impair hippocampal functions.<ref name=":14" /> This suppression would contribute to diminished memory performance and the progression of AD,<ref name=":14" /> while the progression of AD would further aggravate sleep disturbances.<ref name=":14" />

Changes in sleep architecture in patients with AD occur during the preclinical phase of the disease.<ref name=":14" /> These changes could potentially be used to detect those most at risk of developing AD.<ref name=":14" /> However, this is still only theoretical.

While the exact mechanisms and causal relationship between sleep disturbances and AD remain unclear, these findings provide a better understanding and offer possibilities to improve targeting of at-risk populations, as well as the implementation of treatments to curb the cognitive decline of AD patients.