Sleep disturbances and Alzheimer’s Disease
More than 70% of people with dementia are affected by Alzheimer's disease (AD).[31] Despite this high number, our understanding of the mechanisms underlying the progression of this disease remains very limited.[31] However, recent studies have highlighted a link between sleep disturbances and Alzheimer's disease.
Sleep changes with normal aging.[32] Indeed, with age, we find a decrease in time sleeping and also a decrease in the quantity of NREM sleep, more precisely in NREM SWS (less than 10% of the SWS is maintained).[32] Older people also are more prone to insomnia or sleep apnea.[32]
In Alzheimer's disease, in addition to cognitive decline and memory impairment, there is also significant sleep disturbances with a modified sleep architecture.[32][31] The latter may consist in sleep fragmentation, a reduction in sleep duration, insomnia, an increase in daytime napping, a decreased quantity of some sleep stages, and a resemblance between some sleep stages (N1 and N2).[31] More than 65% of people with Alzheimer's disease suffer from this type of sleep disturbance.[31]
One factors that could explain this change in sleep architecture is a change in circadian rhythm, which regulates sleep.[31] A disruption of the circadian rhythm would therefore generate sleep disturbances.[31] Some studies show that people with AD have a delayed circadian rhythm, whereas in normal aging we will find an advanced circadian rhythm.[31][33]
In addition to these psychological symptoms, at a neurological level there are two main symptoms of Alzheimer's disease.[32][31] The first is an accumulation of beta-amyloid waste forming aggregate “plaques”.[31][32] The second is an accumulation of tau protein.[31][32]
Interestingly, it has been shown that the sleep-wake cycle acts on the beta-amyloid burden which is a central component found in AD.[31][32] Indeed, during waking, the production of beta-amyloid protein will be more consistent than during sleep.[31][32][34] This is explained by two phenomena. The first is that the metabolic activity will be higher during waking and thus will secrete more beta-amyloid protein.[31][32] The second is that oxidative stress will also be higher and lead to increased AB production.[31][32]
On the other hand, it is during sleep that beta-amyloid residues are degraded to prevent plaque formation.[31][32][34] It is the glymphatic system that is responsible for this and this phenomenon is called glymphatic clearance.[31][32][34] Thus, during wakefulness, the AB burden is greater because the metabolic activity and oxidative stress are higher and there is no degradation of the protein by the glymphatic clearance whereas during sleep, the burden will be smaller as there will be less metabolic activity and oxidative stress in addition to the glymphatic clearance that occurs at this time.[32][31]
Interestingly, the glymphatic cleanrance occurs during the NREM sleep, and more specifically the NREM SWS sleep.[31][32][34] As seen previously, it is a sleep stage that decreases in normal aging.[32] So there is less glymphatic clearance and an increase in AB burden that will form the AB plaques.[34][31][32] Therefor, in AD sleep disturbances will amplify this phenomenon.
The decrease in the quantity and quality of the NREM SWS as well as the disturbances of sleep will therefore increase the AB plaques.[31][32] This will first take place at the hippocampus level, from which memory is dependent.[31][32] This will result in cell death at this level and will contribute to diminished memory performances and cognitive decline found in AD disease.[31]
Although we do not know the causual relationship, we know that the more the AD progresses, the more we find sleep disorders.[31] In the same way, the more sleep disorders there are, the more the disease progresses, forming a vicious circle.[31] Taken this into account, sleep disturbances are no longer a symptom of AD and relationship between sleep disturbances and AD is bidirectional
In Alzheimer's disease, in addition to cognitive decline and memory impairment, there is also significant sleep disturbances with a modified sleep architecture.[32][31] The latter may consist in sleep fragmentation, a reduction in sleep duration, insomnia, an increase in daytime napping, a decreased quantity of some sleep stages, and a resemblance between some sleep stages (N1 and N2).[31] More than 65% of people with Alzheimer's disease suffer from this type of sleep disturbance.[31]
One factors that could explain this change in sleep architecture is a change in circadian rhythm, which regulates sleep.[31] A disruption of the circadian rhythm would therefore generate sleep disturbances.[31] Some studies show that people with AD have a delayed circadian rhythm, whereas in normal aging we will find an advanced circadian rhythm.[31][33]
In addition to these psychological symptoms, at a neurological level there are two main symptoms of Alzheimer's disease.[32][31] The first is an accumulation of beta-amyloid waste forming aggregate “plaques”.[31][32] The second is an accumulation of tau protein.[31][32]
Interestingly, it has been shown that the sleep-wake cycle acts on the beta-amyloid burden which is a central component found in AD.[31][32] Indeed, during waking, the production of beta-amyloid protein will be more consistent than during sleep.[31][32][34] This is explained by two phenomena. The first is that the metabolic activity will be higher during waking and thus will secrete more beta-amyloid protein.[31][32] The second is that oxidative stress will also be higher and lead to increased AB production.[31][32]
On the other hand, it is during sleep that beta-amyloid residues are degraded to prevent plaque formation.[31][32][34] It is the glymphatic system that is responsible for this and this phenomenon is called glymphatic clearance.[31][32][34] Thus, during wakefulness, the AB burden is greater because the metabolic activity and oxidative stress are higher and there is no degradation of the protein by the glymphatic clearance whereas during sleep, the burden will be smaller as there will be less metabolic activity and oxidative stress in addition to the glymphatic clearance that occurs at this time.[32][31]
Interestingly, the glymphatic cleanrance occurs during the NREM sleep, and more specifically the NREM SWS sleep.[31][32][34] As seen previously, it is a sleep stage that decreases in normal aging.[32] So there is less glymphatic clearance and an increase in AB burden that will form the AB plaques.[34][31][32] Therefor, in AD sleep disturbances will amplify this phenomenon.
The decrease in the quantity and quality of the NREM SWS as well as the disturbances of sleep will therefore increase the AB plaques.[31][32] This will first take place at the hippocampus level, from which memory is dependent.[31][32] This will result in cell death at this level and will contribute to diminished memory performances and cognitive decline found in AD disease.[31]
Although we do not know the causual relationship, we know that the more the AD progresses, the more we find sleep disorders.[31] In the same way, the more sleep disorders there are, the more the disease progresses, forming a vicious circle.[31] Taken this into account, sleep disturbances are no longer a symptom of AD and relationship between sleep disturbances and AD is bidirectional
At the same time, it has been shown that memory consolidation in long-term memory (which depends on the hippocampus) occurs during NREM sleep.[31][35] This indicates that a decrease in the NREM sleep will result in less consolidation and therefore poorer memory performances in hippocampal-dependent long-term memory.[31][35] This drop in performance is one of the central symptoms of AD.[31]
Recent studies have also linked sleep disturbances, neurogenesis and AD.[31] Indeed, it is now known that neurogenesis exists and that the subgranular zone and the subventricular zone keep on creating new neurons even in an adult brain.[31][36] These new cells are then incorporated into neuronal circuits and interestingly, the supragranular zone is found in the hippocampus.[31][36] These new cells will contribute to learning and memory and will play a role in the hippocampal-dependent memory.[31]
Recent studies, however, have shown that several factors can interrupt this neurogenesis.[31] These include stress and prolonged sleep deprivation (more than one day).[31] The sleep disturbances encountered in AD could therefore suppress neurogenesis and thus impairing hippocampal functions.[31] This would therefore contribute to diminished memory performances and the progression of AD.[31] And progression of AD would aggravate sleep disturbances.[31] It is a second vicious circle.
Finally, an interesting aspect is that the changes in sleep architecture found in patients with AD occur during the preclinical phase of AD.[31] These changes could be used to detect those most at risk of developing AD.[31] However, this is still only theoretical.
Although the exact mechanisms and the causal relationship between sleep disturbances and AD are not yet clear, these findings already provide a better understanding. In addition, they open up ideas for the implementation of treatments to curb the cognitive decline of patients suffering from this disease. In the same way, it also makes it possible to better target at risk population.
Recent studies have also linked sleep disturbances, neurogenesis and AD.[31] Indeed, it is now known that neurogenesis exists and that the subgranular zone and the subventricular zone keep on creating new neurons even in an adult brain.[31][36] These new cells are then incorporated into neuronal circuits and interestingly, the supragranular zone is found in the hippocampus.[31][36] These new cells will contribute to learning and memory and will play a role in the hippocampal-dependent memory.[31]
Recent studies, however, have shown that several factors can interrupt this neurogenesis.[31] These include stress and prolonged sleep deprivation (more than one day).[31] The sleep disturbances encountered in AD could therefore suppress neurogenesis and thus impairing hippocampal functions.[31] This would therefore contribute to diminished memory performances and the progression of AD.[31] And progression of AD would aggravate sleep disturbances.[31] It is a second vicious circle.
Finally, an interesting aspect is that the changes in sleep architecture found in patients with AD occur during the preclinical phase of AD.[31] These changes could be used to detect those most at risk of developing AD.[31] However, this is still only theoretical.
Although the exact mechanisms and the causal relationship between sleep disturbances and AD are not yet clear, these findings already provide a better understanding. In addition, they open up ideas for the implementation of treatments to curb the cognitive decline of patients suffering from this disease. In the same way, it also makes it possible to better target at risk population.
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