Sleep and Alzheimer's disease

Introduction

Alzheimer’s disease is a disorder of the brain that affects the thoughts, memory, ability to conduct daily activities, as well as the speech of those individuals affected. It is as a result of this condition that there is also a disruption of the sleep cycle in such a way that it has the potential of bringing about sleep problems and agitation. While it is not a normal part of aging, Alzheimer’s disease has the potential of affecting those individuals who are aging, with risks increasing every five years after the aging individuals turn 60. As a result of the increasing number of aging individuals, the risk of the prevalence of this condition going up has become a public health issue that needs to be addressed satisfactorily to ensure that preventative measures are put in place. The amount of sleep disruption in patients suffering from Alzheimer’s disease is highly dependent on the stage of their disease with those at the early stages sleeping more than normal and ending up being disoriented when they wake. The progression of this disease causes those affected to sleep more during the day and wake up frequently throughout the night. Studies have shown that those patients with advanced Alzheimer’s tend to sleep for only short periods and instead, they end up dozing irregularly during both the day and night. Under such circumstances, among older adults whose circadian rhythms are disrupted, having Alzheimer’s disease often leads to a situation where the disruption is significantly worse to such an extent that it leads to patients being unable to stay asleep. Additionally, there is the potential of losing the ability to keep alert as the disease progresses; causing increasing instances of agitation among patients. This paper seeks to make a connection between sleep disturbances and Alzheimer’s disease through a study of the characteristics of orexin, Amyloid β-Protein, and ApoE genotype and how they respond in individuals with Alzheimer’s disease.

Hypocretin (Orexin)

Those individuals who suffer from moderate to severe Alzheimer’s tend to be kept awake as a result of a neurotransmitter that becomes active at night. Among these individuals, the cerebrospinal fluid levels of orexin, a peptide transmitter whose role is to stave off sleep, becomes highly elevated (Inutsuka & Yamanaka, 2013). This situation is often accompanied by bouts of wakefulness in the early hours of the morning; a sign that there is a level of neurodegeneration. Therefore, an elevation in the levels of orexin plays a significant role in bringing about sleep disturbances associated with Alzheimer’s. The elevation of orexin levels in turn tend to bring about the continued advancement of Alzheimer’s to such an extent that it eventually ends up becoming worse. Therefore, there is a relationship between sleep, orexin and Alzheimer’s in such a way that the first two might have a significant effect on the way that Alzheimer’s develops. Information that was found in studies conducted on Alzheimer’s show that the orexinergic system is directly involved in sleep disturbance especially among individuals with moderate and severe symptoms of the disease to such an extent that it plays a crucial role in the continued severity of Alzheimer’s (Lucey & Holtzman, 2014). The result is that there is an interference with the circadian system which is involved in determining the sleep/wake cycle; making it highly difficult for those individuals affected with Alzheimer’s to achieve deep sleep. The lack of proper sleep is, consequentially, a basic aspect of Alzheimer’s and the treatment of the symptoms involved in the disruption of the sleep cycle could go a long way towards the management of this disease.

Among the most important aspects of orexin is that it is involved in the modulation of the sleep-wake cycle, and as a result, when its functions are interrupted, there is an increase in the risk that it is likely to precede Alzheimer’s (Finn, 2014). This disease is also often accompanied by sleep disturbances to such an extent that those affected end up not being able to have a normal sleep pattern. There has been some speculation that the interruption in sleep patterns are responsible for the hastening of the onset of Alzheimer’s, although the extent to which it is involved is yet to be fully understood. Further studies have shown that for those individuals who suffer from Alzheimer’s , there is often a considerable retention in the Amyloid β-Protein levels during a night’s sleep, which is not the case with people with regular sleeping patterns whose Amyloid β-Protein levels drop significantly as they sleep. Tests conducted on mice have shown that when they lack sleep, their Amyloid β-Protein deposition is highly accelerated and the presence of orexin acts as a booster for Amyloid β-Protein levels (Huang, Potter, Sigurdson, Santacruz, Shih, Ju, Kasten, Morris, Mintun, Duntley & Bateman, 2012). Thus, the presence of orexin is a factor in the increase in the levels of Amyloid β-Protein among those individuals who suffer from a lack of sleep. In the case of Alzheimer’s patients, the lack of regular sleep keeps on increasing the Amyloid β-Protein levels, and it is most likely as a result that this disease ends up being accelerated since the individuals affected by it are not able to have much needed sleep.

Hyperactivity in orexinergic neurons in the hypothalamus is suspected to be behind the sleep deprivation among those individuals experiencing neurodegeneration. There is an extremely dangerous relationship between Amyloid β-Protein and sleep deprivation which leads to the acceleration of Alzheimer’s  because the neurodegeneration that comes about as a result tends to damage those parts of the brain that are responsible for the proper governance of sleep (Ooms, Overeem, Besse, Rikkert, Verbeek & Claassen, 2014). The far-reaching effects of the orexinergic neurons deliver the neuropeptide known as hypocretin to many parts of the brain’s regions, which bring about wakefulness. A study shows that while narcoleptics have abnormally low levels of orexin, it does not protect them from the development of Alzheimer’s. This situation means that even with low levels of orexin, they still have a significant effect on the wakefulness of individuals affected with Alzheimer’s  and might make the condition worse.

Amyloid β-Protein

In a study aimed at finding out the relationship between Alzheimer’s  biomarkers, orexin, cognition, and sleep quality, the findings showed that there was a substantial upsurge in cerebrospinal fluid (CSF) total tau alongside orexin levels (Bateman, Wen, Morris & Holtzman, 2007). While there was no direct connection found between Amyloid β-Protein and orexin levels, they both seem to be related to the reduction of sleep quality. This is especially considering that the waning of Amyloid β-Protein levels and an increase in orexin levels has the result of leading to a lack of deep sleep (Dauvilliers, Lehmann, Jaussent, & Gabelle, 2014). When it comes to cognition, those individuals with Alzheimer’s who have the least sleep tend to have even lower levels of cognition. Hence, there is a direct link between the worsening of Alzheimer’s and lack of sleep as a result of a reduction of Amyloid β-Protein levels. Alzheimer’s also seems to be made worse considering that waning Amyloid β-Protein levels makes it more difficult for individuals affected to gain deep sleep; meaning that there is an increase in the risk of neurodegeneration (Zlokovic, Deane, Sallstrom, Chow, & Miano, 2005). The severity of Alzheimer’s  can be considered to be one of the reasons behind the maintenance or reduction of Amyloid β-Protein levels because while those with moderate symptoms show less severe waning of Amyloid β-Protein levels, those with more severe symptoms end up not being able to sleep comfortably as a result of the massive neurodegeneration taking place. Moderate and severe Alzheimer’s patients tend to display the same symptoms of irregular sleep patterns that not only have an effect on cognition, but also make the condition worse.

Alzheimer’s is often heralded and accompanied by sleeping problems and this is a highly consequential issue when it comes to the study of the disease. The deposition of Amyloid β-Protein levels, in this case, makes it difficult for that suffering from Alzheimer’s to gain deep sleep and as a result, the disease becomes even worse. Evidence from studies increasingly show that the Amyloid β-Protein is an important player when it comes to the causation of Alzheimer’s  and that it is essential to ensure that it is used as a therapeutic purposes because it is highly tractable (Fagan, et al., 2006). Amyloid β-Protein has the ability to self-associate in a way that ends up forming oligomeric assemblies that are often behind the development of the toxic events that lead to significant memory impairment in those affected, which is later followed by neurodegeneration. Therefore, Amyloid β-Protein can be considered to be a key influence in the development of Alzheimer’s because it brings about a situation where patients end up having high levels of toxicity which affects their memories. This, combined with the high orexin levels that often come about later in the disease, leads to the further advancement of Alzheimer’s to such an extent that the patients involved are no longer able to have proper sleep patterns. The lack of sleep, in turn, exacerbates the problem because it Alzheimer’s becomes even worse as a result; making it difficult for those affected to remain calm, especially at night when they become increasingly agitated.

The accumulation of Amyloid β-Protein in the brain tends to start years prior to the clinical commencement of Alzheimer’s, showing that it is a factor in the development of this disease. Before the aggregation process begins, the levels of extracellular, soluble interstitial fluid Amyloid β-Protein tends to correlate with the level of Amyloid β-Protein deposition that is witnessed later in the patient’s brain. The soluble interstitial fluid Amyloid β-Protein is regulated by both neuronal activity and the sleep-wake cycle and it is the disruption of this cycle that leads to the increasing severity of Alzheimer’s. As a result, the amount of sleep time as well as its quality continues to decline despite as the individual ages, and to a greater extent through the advent of Alzheimer’s. While this may be the case, the connection between changes in Amyloid β-Protein with age as well as the aggregation of Amyloid β-Protein has yet to be completely understood, meaning that more research has to be conducted in this area. Studies have shown that normal sleep-wake cycle and diurnal fluctuation of interstitial fluid Amyloid β-Protein is present in the brain before the plaque formation of Amyloid β-Protein (Lucey & Bateman, 2014). Following plaque formation, there is a significant deterioration in the sleep-wake cycle which is accompanied by the dissipation of interstitial fluid Amyloid β-Protein. Amyloid β-Protein aggregation has a disruptive effect on the sleep-wake cycle and circadian instability of Amyloid β-Protein; showing that the sleep-wake behavior of an individual and diurnal fluctuation of Amyloid β-Protein in the central nervous system are functional markers for the development of Alzheimer’s .

ApoE Genotype

Alzheimer’s is the most common form of dementia whose symptoms include Amyloid β-Protein plaques neurological loss, and inflammation. There is a powerful genetic factor in the development of Alzheimer’s that is exemplified by the Apolipoprotein E4 (ApoE4) allele (Cored, Saunders, Risch, et al., 1994; Hauser & Ryan, 2013). The ApoE2 allele, on the other hand, is protective although there are instances where it might predispose individuals to cerebral amyloid angiopathy (Lemmens, Görner, Schrooten, & Thijs, 2007; Nelson, Pious, Jicha, Wilcock, Fardo, Estus, & Rebeck, 2013). The result of this predisposition is that it ends up leading to risk factors involving brain hemorrhage or white matter disease. Sleep disordered breathing and Alzheimer’s  share a number of common characteristics, such as vascular disease, although sleep disordered breathing tends to be increasingly prevalent in cases of severe Alzheimer’s, with the ApoE4 allele having additional effects (Gehrman, Martin, Shochat, Nolan, Corey-Bloom & Ancoli-Israel, 2003; Osorio, Ayappa, Mantua, et al., 2014). Therefore, the treatment of sleep disordered breathing has a positive effect on restoring the sleep patterns of individuals with Alzheimer’s , while at the same time also being important in improving cognition; which is normally decreased as a result of the development of Alzheimer’s. While a connection between sleep disordered breathing and Alzheimer’s  has been established, research concerning this connection has not born fruit because studies that bring about a definitive diagnosis can only be conducted postmortem (Spira, Blackwell, Stone, Redline, Cauley, Ancoli-Israel &Yaffe, 2008). However, the connection between the ApoE allele and Alzheimer’s  is based on the former posing a significant risk factor for the development of Alzheimer’s because it has the potential of leading to neurodegeneration as a result of brain hemorrhage and white matter disease.

 The severity of sleep disordered breathing is reflected through lower CSF Amyloid β-Protein 42 levels. Thus, those individuals with advanced preclinical Alzheimer’s  are most likely to have significant sleep disordered breathing as a result of the predisposition of ApoE4+ (Sperling, Aisen, Beckett, Bennett, Craft & Fagan, 2011). Studies have found that individuals with ApoE4+ tend to present lower concentrations of Amyloid β-Protein 42 and higher T-Tau and P-Tau than ApoE3+ at any cognitively defined disease stage (De Santi, Pirraglia, Barr, Babb, Williams, et al., 2008). While about 40 – 65% of those patients suffering from Alzheimer’s have at least a replica of the ApoE4 allele, this gene is not determinant of the development of this disease and in some instances; the homozygotes that contain this gene do not develop the disease (Leoni, 2011). However, those with two ApoE4 alleles run a significant risk of developing Alzheimer’s as they grow older and this risk can go as high as twenty times of those who have only a single allele. Hence, those who have two alleles are most likely to develop this disease at an earlier age than their counterparts and might display the symptoms which include sleep disturbances (Lim, Kowiger, Schneider, et al, 2013). The irregular sleep patterns that are displayed in individuals with the ApoE4 allele marks the advent of Alzheimer’s and it is only through taking steps aimed at controlling the symptoms that come about as a result of lack of sleep, such as cognition problems, that severe lack of sleep can also be alleviated.

Strategies for Management

There are various strategies through which the sleep-wake cycle can be restored or managed among those individuals suffering from Alzheimer’s , and these include nonpharmacological and pharmacological treatments as well as studies of neuropeptide Y. Nonpharmacological treatment options involves attempts to ensure that there is an improvement in the sleep routine and the sleeping environment of the individuals affected by Alzheimer’s . Nonpharmacological treatments have to be tried before any attempt is made to prescribe medications because some sleep medications have some serious side effects. One of the most constructive nonpharmacological means involves seeking sunlight exposure which ensures that the sleep-wake cycle is reestablished on a daily basis. Avoiding alcohol, caffeine or nicotine is also essential in the development of conditions necessary for attaining deep sleep. However, there are instances where pharmacological means have to be applied to deal with the disruption of the sleep-wake cycle. Among these is the use of tricyclic antidepressants such as trazodone or antipsychotics, although all these have to be prescribed according to the behaviors that accompany sleep changes that patients display (Urrestarazu & Iriarte, 2016). The use of antipsychotics has to be done as a last resort because they bring with them a lot of health risks and side effects such as the possibility of having a stroke or death, especially among the elderly who have dementia. Neuropeptide Y studies could also go a long way towards helping in the development of treatment for sleep disturbances among Alzheimer’s patients, because as a neurotransmitter to the brain, it has an effect on Circadian rhythm, which is in turn affected by external stimuli.

References

Bateman, R.J., Wen, G., Morris, J.C., & Holtzman, D.M. (2007). Fluctuations of CSF amyloid-beta levels: implications for a diagnostic and therapeutic biomarker. Neurology, 68(9), 666-9.

Corder, E.H., Saunders, A.M., Risch, N.J., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Rimmler, J.B., Locke, P.A., Conneally, P.M., Schmader, K.E., et al. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet., 7, 180–114.

Dauvilliers, Y.A., Lehmann, S., Jaussent, I., & Gabelle, A. (2014). Hypocretin and brain β-amyloid peptide interactions in cognitive disorders and narcolepsy. Front Aging Neurosci, 6, 119.

De Santi, S., Pirraglia, E., Barr, W.B., Babb, J., Williams, S., Rogers, K., Glodzik, L., Brys, M., Mosconi, L., Reisberg, B., Ferris, S., & de Leon, M.J., 2008). Robust and conventional neuropsychological norms: Diagnosis and prediction of age-related cognitive decline. Neuropsychology, 22, 469–84.

Fagan, A. M. et al. (2006). Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol. 59, 512–519.

Finn, M.B. (2014). Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease. JEM, 211(13), 2487-2496.

Gehrman, P.R., Martin, J.L., Shochat, T., Nolan, S., Corey-Bloom, J., & Ancoli-Israel, S. (2003). Sleep-disordered breathing and agitation in institutionalized adults with Alzheimer disease. Am J Geriatr Psychiatry, 11, 426–33.

Hauser, P.S. & Ryan, R.O. (2013). Impact of apolipoprotein E on Alzheimer's disease. Current Alzheimer Research, 10(8), 809–17.

Huang, Y., Potter, R., Sigurdson, W., Santacruz, A., Shih, S., Ju, Y., Kasten, T., Morris, J.C., Mintun, M., Duntley, S., & Bateman, R.J. (2012). Effects of age and amyloid deposition on Aβ dynamics in the human central nervous system. Arch Neurol., 69, 51–8.

Inutsuka, A. & Yamanaka, A. (2013).The regulation of sleep and wakefulness by the hypothalamic neuropeptide orexin/hypocretin. Nagoya J Med Sci., 75(1-2), 29-36.

Kang, J.E., Lim, M.M., Bateman, R.J., Lee, J.J., Smyth, L.P., Cirrito, J.R., Fujiki, N., Nishino, S., & Holtzman, D.M. (2009). Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science, 326(5955), 1005-7.

Lemmens, R., Görner, A., Schrooten, M., & Thijs, V. (2007). Association of apolipoprotein E epsilon2 with white matter disease but not with microbleeds. Stroke, 38, 1185–8.

Leoni, V. (2011). The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer's disease. Clin Chem Lab Med., 49, 375–83.

Lim, A.S.P., Kowiger, M., Schneider, J.A., et al. (2013). Sleep Modifies the Relation of APOE to the Risk of Alzheimer Disease and Neurofibrillary Tangle Pathology. JAMA Neurol., 70(12): 10.1001/jamaneurol.2013.4215.

Lucey, B.P. & Bateman, R.J. (2014). Amyloid-β diurnal pattern: possible role of sleep in Alzheimer's disease pathogenesis. Neurobiol Aging, 35(2), 29-34.

Lucey, B.P. & Holtzman, D.M. (2014).Sleep and Alzheimer disease pathology - a bidirectional relationship.  Nature Reviews Neurology, 10, 115–119.

Nelson, P.T., Pious, N.M., Jicha, G.A., Wilcock, D.M., Fardo, D.W., Estus, S., & Rebeck, G.W. (2013). APOE-ε2 and APOE-ε4 correlate with increased amyloid accumulation in cerebral vasculature. J Neuropathol Exp Neurol., 72, 708–15.

Ooms, S., Overeem, S., Besse, K., Rikkert, M.O., Verbeek, M., & Claassen, J.A. (2014). Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol, 71(8), 971-7.

Osorio, R., Ayappa, I., Mantua, J., et al. (2014). The interaction between sleep-disordered breathing and ApoE genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly. Neurobiol Aging, 35(6), 1318–1324.

Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, D.A., Craft, S., & Fagan, A.M. (2011). Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement., 7, 280–92.

Spira, A.P., Blackwell, T., Stone, K.L., Redline, S., Cauley, J.A., Ancoli-Israel, S., &Yaffe, K. (2008). Sleep-disordered breathing and cognition in older women. J Am Geriatr Soc., 56, 45–50.

Urrestarazu, E. & Iriarte, J. (2016).Clinical management of sleep disturbances in Alzheimer's disease: current and emerging strategies. Nat Sci Sleep, 8, 21-33.

Zlokovic, B.V., Deane, R., Sallstrom, J., Chow, N., & Miano, J.M. (2005). Neurovascular pathways and Alzheimer amyloid beta-peptide. Brain Pathol., 15(1), 78-83.