1. Introduction

Alzheimer’s disease is the most common cause of dementia. Dementia is a clinical syndrome characterized by loss of function in more than one cognitive domain, interfering with personal, social, and work-related functionality [Viñuela et al., 2009].

Degenerative dementias are diseases characterized by the loss of neurons and synapses as well as by the intracellular and/or extracellular deposition of insoluble protein aggregates in the brain. Each type of protein deposit tends to follow a topographical pattern that correlates with the clinical characteristics that define each type of dementia.

Alzheimer’s disease accounts for 60% to 80% of all cases of dementia in persons older than 65 years [Winblad et al., 2016]. Worldwide, about 47 million people currently have Alzheimer’s disease, and this figure is expected to reach 130 million in 2050 [Prince et al., 2015]. In Spain, current estimates are between 400,000 and 600,000; these figures are expected to reach 1 million in 2050. The incidence in Europe ranges from 7.7 to 23.8/1000 inhabitants/year; in Spain, it is estimated at 10.8/1000 inhabitants/year in all persons aged 75 years and up [López-Pousa et al., 2004] and 7.4/1000 inhabitants/year in those aged between 65 and 90 years [Bermejo-Pareja et al., 2008]. The prevalence increases exponentially with age, ranging from 6% to 8% at 65 years and increasing to 30% at 85 years [Prince et al., 2013]. Although studies in developed countries show that the progressive increase in the incidence of Alzheimer’s disease has slowed considerably, possibly due to improved control of cardiovascular risk factors in recent decades, Alzheimer’s disease will have an increasing impact on healthcare, social relations, and the economy [Chibnik et al., 2017].

The pathophysiology of Alzheimer’s disease is still poorly understood. Pathology studies reveal extracellular deposits of beta-amyloid peptide (senile plaques) and intracellular deposits of hyperphosphorylated tau protein (neurofibrillary tangles) together with synaptic dysfunction, neuron loss, and gliosis. Of all these findings, amyloid accumulation is the earliest and most specific for Alzheimer’s disease, so it is considered a necessary element for the development of the entire pathophysiological process that is triggered either by overproduction in the hereditary types and/or decreased clearing in the sporadic types.

The main risk factors are age and female sex. All cardiovascular risk factors, including obesity, are also risk factors for Alzheimer’s disease, establishing a complex, unequivocal relation between cerebral vascular disease and Alzheimer’s disease [Kivipelto et al., 2005; Craft, 2009; Gottesman et al., 2017]. Finally, individuals with a history of head injury and those with Down’s syndrome also have an increased risk of developing Alzheimer’s disease, in the latter group due to trisomy of the 21st chromosome, where the amyloid precursor protein is coded.

Hereditary types represent only 1% of all cases of Alzheimer’s disease. The genes associated with the hereditary types are the presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2) genes, as well as the amyloid protein precursor gene (APP). Among the genetic risk factors, the most important seems to be the presence of the ε4 allele of the apolipoprotein E gene (APOE).

At the clinical level, Alzheimer’s disease is characterized by the loss of episodic memory secondary to hippocampal involvement in association with other abnormalities in cortical function, such as apraxia, aphasia, agnosia, or disturbed executive and visuospatial functions as the disease progresses. In some cases, there can be other presentations in which frontal symptoms, language abnormalities, or visual agnosia predominate.

The disease also courses with neuropsychiatric and behavioral symptoms that cause the greatest burden on caregivers as the disease progresses, and these symptoms are directly related with the risk of institutionalization. These symptoms include apathy or depression, which can be present in the initial stages of the disease or even precede the appearance of amnesic symptoms. Later, other clinical manifestations appear, such as anxiety, wandering, irritability, appetite alterations, delirious ideas, and visual or, less frequently, auditory hallucinations. Sleep disturbances are also common.

Sleep disorders are present in 40% to 65% of persons with Alzheimer’s disease who live in the community [McCurry et al., 1999; Rongve et al., 2010], and they represent a significant burden for caregivers, high healthcare costs, and higher rates of institutionalization [Gaugler et al., 2000].

During aging, physiological changes in sleep occur, including 1) phase advance, with earlier sleep onset and awakening; 2) greater sleep latency; 3) decreased total sleep time; 4) greater sleep fragmentation; 5) more fragile sleep; 6) lesser proportion of deep sleep; 7) greater proportion of light sleep (N1 and N2); 8) fewer and shorter NREM-REM cycles, and 9) a greater amount of time awake during the night [Bliwise, 2005; Mander et al., 2017].  In Alzheimer’s disease, a phase delay occurs during nocturnal sleep, the opposite of the phase advance that occurs during normal aging. The other changes are more accentuated in patients with Alzheimer’s disease compared to subjects of the same age who do not have the disease.

Although sleep disorders tend to worsen as the disease progresses, the type of sleep disorders and their impact on the patient depend on the stage of disease. Insomnia is the most common symptom, and it is found in all stages of Alzheimer’s disease. In the presymptomatic stage, when patients have yet to develop cognitive problems but biomarkers show beta-amyloid deposits, subjects have less efficient sleep [Ju et al., 2013], increased sleep latency [Brown et al., 2016], and excessive daytime sleepiness [Carvalho et al., 2018]. Patients with cognitive deterioration have changes in sleep architecture, with decreased sleep spindles and a smaller proportion of deep sleep. Finally, during the stage of mild-moderate dementia, subjects have 1) insomnia and fragmented sleep (longer periods in which they are awake during the night), as the most frequent symptoms; 2) sundowning syndrome; 3) nocturnal walking and wandering; and 4) excessive daytime sleepiness with frequent napping.

Table 1 lists the most common sleep disturbances

SUBJECTIVE
Conciliation insomnia
Sleep fragmentation
Excessive daytime sleepiness
Nocturnal walking or wandering

Sundowning syndrome

Sleep disorders that are often concomitant with Alzheimer’s disease: sleep apnea/hypopnea syndrome, restless legs syndrome, periodic limb movements that can disturb sleep.
OBJECTIVE
Circadian rhythm disorder
Less total time sleeping and less efficient sleep

Decreased proportion of deep sleep

Prolonged latency of REM sleep

Frequent arousals during the night

Periodic limb movements
Hypersomnia

 

The relation between sleep and Alzheimer’s disease is complex and multifactorial. From an anatomical point of view, the following brain structures are involved:

  1. Atrophy of the suprachiasmatic nuclei, the principal structure responsible for maintaining circadian rhythms, with volume loss and loss of cells [Swaab et al., 1985]. In advanced disease, there may be neurofibrillary tangles and a decreased number of neurons of that express melatonin receptors [Wu et al., 2007].
  2. Involvement of the cholinergic system (the nucleus basalis of Meynert and laterodorsal tegmental nucleus) and of noradrenergic neurons responsible for regulating REM sleep [Grothe et al., 2012; Theofilas et al., 2017]. These structures are also involved in apneas of central origin and daytime sleepiness.
  3. Hypothalamic dysregulation involving the secretion of hypocretin, giving rise to greater daytime sleepiness [Liguori et al., 2014]

2. Role of sleep in the pathogenesis of Alzheimer's disease

In physiological conditions, sleep plays a role in brain maturation and cognitive development. The quantity and quality of sleep can influence the maintenance of cognitive functions such as memory consolidation and learning [Karni et al., 1994].  The different phases of sleep have an important role in each of the cognitive processes. Thus, deep sleep favors memory consolidation dependent on hippocampal activity [Born et al., 2006], whereas REM sleep is especially important for consolidating procedural memory, as there is a proven connection between cerebral cholinergic activity, the time and the density of REM sleep, and executive performance [Spiegel et al., 1999].

Alterations in the quantity or quality of sleep and excessive daytime sleepiness are associated with the development of cognitive decline [Jaussent et al., 2012; Miller et al., 2014; Elcombe et al., 2015; Tsapatou et al., 2015].

There is a bidirectional relationship between sleep disturbances and Alzheimer’s disease. On the one hand, amyloid production and clearance follows a circadian rhythm—its production increases during the day, whereas during nocturnal sleep, more specifically during slow-wave sleep, its production decreases and clearance increases. Moreover, although less evidently, clearance of tau protein, the other biomarker of the disease, increases during slow-wave sleep. Thus, sleep fragmentation could increase the levels of beta-amyloid and with time increase the risk of senile plaque formation. One study showed a relation between the presence of amyloid deposits and a decrease in the total amount of sleep reported [Spira et al., 2013], and another found a relation between deposits and less sleep efficiency [Yu et al., 2013]. Excessive daytime sleepiness has also been associated with the presence of cerebral amyloid in neuroimaging studies [Carvalho et al., 2018]. On the other hand, the dysfunction caused by Alzheimer’s disease results in greater sleep-arousal instability and more arousals, which can increase daytime sleepiness and consequently reduce daytime physical activity and favor obesity, which are both risk factors for Alzheimer’s disease. Thus, there is a vicious circle in which the disease perpetuates sleep disturbances and sleep disturbances favor the progression of the disease.

A paradigmatic example of this situation is obstructive sleep apnea syndrome (SAHS), which increases the risk of dementia [Yaffe et al., 2011; Leng et al., 2017]. SAHS causes episodes of sleep fragmentation and of intermittent hypoxia followed by an episode of reoxygenation. Through sleep fragmentation, this can hinder amyloid clearance, triggering the entire chain of events, and the phenome related to hypoxia-reoxygenation can increase the risk of oxidative damage and favor inflammatory processes that facilitate the development of Alzheimer’s disease.

3. Sleep problems in Alzheimer's disease

Sleep disorders in Alzheimer’s disease can be classified into three major groups:

a.      Altered circadian rhythms

In Alzheimer’s disease, biological rhythms are disturbed and these disturbances increase with disease progression, manifesting as nocturnal insomnia and excessive daytime sleepiness [Videnovic et al., 2014]. Both difficulties in falling asleep at night and waking up at night can unleash episodes of walking around the house and wandering at night, with the consequent risk of falls and injuries, so this is one of the reasons for institutionalizing these patients [Bombois et al., 2010]. Daytime sleepiness can increase social difficulties and limit adherence to treatment as well as increase the risk of traffic accidents.

 

Patients with Alzheimer’s disease have objectively observable abnormalities in various biologic systems, for example, the control of body temperature, the secretion of melatonin, and their variation with circadian rhythms. Melatonin secretion is lower in patients with Alzheimer’s disease than in healthy subjects of the same age [Zhou et al., 2003] and the rhythm of secretion disappears, resulting in irregular patterns [Skeene and Swadi, 2003]. Various studies have shown that these abnormalities can be found in preclinical and initial phases of the disease [Hatfield et al., 2004; Tranah et al., 2011].

One specific case of altered circadian rhythms is sundowning syndrome, which consists of the appearance or worsening of neuropsychiatric symptoms in the evening in patients with dementia. It manifests as agitation, lessened attention to external stimuli, disorganized thought, motor restlessness, and altered perception such as illusions and hallucinations, anxiety, fear, and anger. Up to 20% of patients with Alzheimer’s disease have sundowning syndrome [Alzheimer’s Association, 2016]. It has a multifactorial origin: neurobiological factors inherent to the disease, as well as pharmacological, physiological, medical and environmental factors [Canevelli et al., 2016]. This syndrome is associated with worse cognitive prognosis, and is a frequent cause of institutionalization because it worsens relations between patients and their families.

 

b.      Changes in sleep architecture

Patients with Alzheimer’s disease have low sleep efficiency, with a greater percentage of N1 (NREM) sleep and a higher frequency of arousals and awakening. Moreover, during NREM they have decreased density of sleep spindles, as well as decreased slow-wave sleep (deep sleep). In some cases, there is a loss of elements characteristic of NREM on tracings, resulting in a pattern of sleep that is difficult to classify (indeterminate sleep). These patients also have prolonged REM latency and a smaller proportion of REM sleep [Bliwise, 1993].

 

c.      Respiratory disorders during sleep

SAHS is found in up to 40% of patients with Alzheimer’s disease living in the community and in up to 70% of those who are institutionalized [Reynolds et al., 1985; Ancoli-Israel et al., 1991]. Several studies have shown that patients with Alzheimer’s disease have a fivefold risk of having SAHS compared to cognitively healthy subjects of similar age [Emamian et al., 2016; Griffith et al., 2017].

 Since there is a specific treatment for SAHS, it is important to note symptoms such as snoring, daytime sleepiness, or apneas and to refer patients quickly for evaluation. Respiratory events, whether snoring, hypopneas, or apneas, can cause micro-arousals or awakening, fragmenting sleep and in some cases triggering episodes of abnormal behavior during the night, mimicking REM sleep behavior disorder [Iranzo and Santamaria, 2005].

 

d.      Other sleep problems

In addition to the above-mentioned sleep problems, other disorders are also more prevalent in patients with Alzheimer’s disease than in the general population, especially restless legs syndrome and periodic limb movements.

Restless legs syndrome is a sensory-motor disorder that is diagnosed clinically. In individuals with cognitive decline, this syndrome merits special consideration because of the limitations they may have in expressing their complaints. For this reason, for the diagnosis of restless legs syndrome, patients must have [Allen et al., 2003]:  1) signs of discomfort, such as massaging their legs or complaining while sustaining their legs; 2) excessive motor activity, for example: walking around the house, restless fidgeting, or tossing and turning in bed; 3) appearance or worsening of signs during periods of rest or inactivity; 4) decrease in or disappearance of signs of physical activity, and 5) criteria 1 and 2 occur only in the evening or at night and worsen at this time of day. The presence of restless legs syndrome and other concomitant sleep problems can contribute to patients’ nocturnal agitation [Rose et al., 2011].

Periodic limb movements are common in older persons [Haba-Rubio et al., 2016]. When these movements fragment sleep, causing insomnia, non-reparative sleep, and daytime sleepiness, this condition is termed periodic limb movements disorder [American Academy of Sleep Medicine, 2014]. Moreover, this disorder can also involve nightmares and abnormal behavior during sleep, simulating REM sleep behavior disorder [Gaig et al., 2017].

4. Evaluating sleep in patients with Alzheimer's disease

It is important to characterize patients’ sleep problems and to determine possible causal factors. As in the general population, the evaluation of sleep in persons with dementia starts with taking a thorough history. It is essential to include the principal caregiver or someone who lives with the patient, since persons with cognitive decline might not remember their symptoms. It is important to take into account spontaneous complaints, schedules, and the regularity of nocturnal sleep and daytime naps  (whether intentional or not).

The clinical history should also record symptoms of sleep disturbances such as snoring, observed apneas, excessive daytime sleepiness, abnormal behaviors during sleep (parasomnias or mimics of parasomnias), and movement disorders (restless legs syndrome and limb movements during sleep). In  addition to this information, specific questions should address behaviors related to sundowning syndrome,  the presence of hallucinations, sleep attacks, false nocturnal recognitions, injuries during nocturnal episodes (parasomnias or mimics of parasomnias), and nocturnal walking and wandering.

Later, specific questions should be asked about different external factors that can cause or aggravate sleep disturbances. Psychiatric comorbidity, such as depression and/or anxiety, pain or discomfort, or other problems that can cause patients to wake up (e.g., frequent urination due to prostatic hypertrophy), can affect nighttime rest. It is important to know what treatments the patient is receiving, including supplements and over-the-counter drugs; current and previous consumption of alcohol, tobacco, caffeine, or other substances; degree, frequency, and regularity of physical activity; social and occupational activity and the schedule for these activities; timetable and regularity of meals; as well as exposure to light and noise during the day and night.

The scales that are usually used to evaluate sleep, such as the Epworth’s Sleepiness Scale [Johns, 1991] or the Pittsburgh Sleep Quality Index [Buysse et al., 1989], have not been specifically validated for use in patients with dementia. There are other scales that are more oriented to caregivers than to patients, such as the Sleep Disturbance Inventory [Tractenberg et al., 2003] or the Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD).

Nocturnal video polysomnography is the technique of choice for evaluating sleep. It makes it possible to diagnose sleep disorders such as SAHS, periodic limb movements disorder, or abnormal behaviors during sleep (parasomnias or sleep disturbances that mimic parasomnias). A family member or caregiver will remain in the sleep laboratory to accompany the patient, since patients can become confused or anxious in an unfamiliar environment in which they are surrounded by sensors, and this could reduce the hours of sleep recorded and decrease the usefulness of the test.

Actigraphy uses portable motion sensors placed on the wrist like a watch to register movement during a 14-day period. The device is an accelerometer that enables us to extrapolate data about activity and resting. It makes it possible to complete the data about patients’ real lives in their habitual environment. It is useful for evaluating sleep-arousal cycles and can provide information about disturbances in circadian rhythms. Actigraphy should be used together with sleep diaries (completed by family members or caregivers), where patients’ daily sleep routines are recorded as well as possible events occurring during the examination period. This technique has a good correlation with the findings about sleep/arousal on polysomnography in institutionalized patients [Ancoli-Israel et al., 1997].

5. Treating sleep problems in patients with Alzheimer's disease

The management of sleep disturbances in persons with dementia has social and clinical implications. There are no specific treatments for sleep problems in patients with Alzheimer’s disease, but it is important to use an individualized therapeutic approach that aims to improve patients’ quality of life and complements interventions designed to favor cognitive function and delay the progression of dementia. When managing sleep problems, it is important to avoid worsening cognitive function, to limit the risk of secondary effects, and to reduce the burden on caregivers.

To achieve these goals, we must take into account:

  1. Educational aspects directed at patients and caregivers about habits and routines, insisting on good sleep hygiene. Bad habits must be corrected and false beliefs must be refuted by providing information and recommendations about how to follow regular hours and trying to avoid long naps. Physical exercise is important for physical and mental health and can favor better nocturnal sleep in adults.
  2. Comorbidities, medications, and consumption of stimulants and sedatives. Other health problems can affect nocturnal rest in patients with Alzheimer’s disease. Pain, limited mobility, and frequent urination at night should be appropriately managed by the patient’s medical team. Psychiatric alterations such as depression or anxiety should also be taken into consideration and treated appropriately. All medications and supplements that can affect sleep should be thoroughly reviewed (e.g., inhaled β2-receptor agonists, diuretics, or acetylcholinesterase inhibitors) and their use should be optimized to ensure that their interference with the wake-sleep cycle is minimal. Furthermore, the consumption of other substances such as caffeine, alcohol, or tobacco that can interfere with the structure of sleep must also be considered.
  3. Specific treatment for sleep disorders:

 

a. Altered circadians rhythms ans insomnia

Few studies have been specifically designed to examine treatments for insomnia in patients with cognitive decline, and those have yielded negative results or scant efficacy. Thus, recommendation should be based not only the scientific evidence of efficacy in these patients, but also on the safety profile of the drugs and the patient’s comorbidities.

Among the non-pharmacological treatments available, cognitive-behavioral therapy and bright light therapy are noteworthy. The latter can improve the quality of sleep and nocturnal activity rhythms [Ancoli-Israel et al., 2003].

Pharmacological treatment should be reserved for refractory cases. In general, hypnotics should be avoided for insomnia because they increase the risk of falls. Studies to gather scientific evidence for drug therapy have been limited to melatonin and trazodone. There is no scientific evidence for the use of other drugs, and they have been associated with adverse effects.

Melatonin yields no benefits for patients with dementia and sleep complaints [Singer et al., 2003; Cardinali et al., 2010]. However, as it has no secondary effects, the use of small nocturnal doses (2-5 mg) melatonin is considered reasonable together with bright light therapy [Riemersma-van der Lek et al., 2008].

Administering 50 mg trazodone has proven to increase the total time sleeping and to improve the efficiency of sleep compared to a placebo, but it does not reduce nocturnal arousals [Camargos et al., 2014].

Although no scientific evidence is available, in clinical practice some drugs are used to control insomnia. The most common are the benzodiazepines and other hypnotics, although they are associated with secondary effects such as daytime sleepiness, worsening of insomnia when treatment is interrupted, confusion, amnesia, abnormal behavior, and increased frequency of falls [Closser, 1991]. In patients with dementia and sleep disorders, especially those who show nocturnal agitation, antipsychotics with sedative effects such as quetiapine or olanzapine have been prescribed, even though they have been shown to increase mortality and can worse cognition. Occasionally, antihistamines are prescribed, but this is not advisable because they have adverse effects.

In patients with excessive daytime sleepiness, physical exercise and social interaction have been shown to increase daytime alertness and improve nocturnal sleep [Benloucif et al., 2004; Richards et al., 2011]. Drugs such as modafinil or methylphenidate have not proven efficacious.

b. Obstructive sleep apnea-hypopnea syndrome

Patients should be assessed for SAHS whenever symptoms are present; if confirmed, SAHS should be treated with continuous positive airway pressure (CPAP) [Weaver and Chasens 2007]. Various clinical trials have shown that treating SAHS improves cognitive function in patients without dementia [Ferini-Strambi et al., 2013]. Some cases of improved cognition and behavior in patients with dementia have been reported. However, few studies have been done, in part because these patients have greater difficulties adapting to treatment and require more attention to ensure good adherence. Different clinical trials have shown the efficacy of CPAP, although insufficient data is available to establish its usefulness in improving cognition in this group of patients [Ayalon et al., 2006; Chong et al., 2006; Ancoli-Israel et al., 2008; Troussiere et al., 2014].

c. Other sleep problems: restless legs syndrome and periodic limb movements disorder

The therapeutic approach is the same for both of these abnormalities. As in the general population, secondary causes (e.g., iron deficiency or renal failure) must be ruled out. After that, patients with mild cognitive deterioration without psychotic symptoms could be considered candidates for standard treatment with dopaminergic agonists. In or patients with advanced disease or hallucinations, treatment with other first-line drugs such as gabapentin o la pregabalin could be considered

6. References

  • Allen R, Picchietti D, Henning W, Trenkwakder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations and epidemiology: a report from the restless legs syndrome diagnosis and epidemiology Workshop at the National Institutes of Health; Sleep Med 2003; 4:101-19.
  • American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014
  • Ancoli-Israel S, Klauber MR, Butters N, Parker L, Kripke DF. Dementia in institutionalized elderly: relation to sleep apnea. J Am Soc 1991;39:258-63.
  • Ancoli-Israel S, Clopton P, Klauber MR, Fell R, Mason W. Use of wrist actigraphy for monitoring sleep/wake in demented nursing home patients. Sleep 1997;20:24–7.
  • Ancoli-Israel S., Gehrman P, Martin JL, Shochat T, Marler M, Corey-Bloom J, et al. Increased light exposure consolidates sleep and strengthens circadian rhythms in severe Alzheimer’s disease patients. Behav Sleep Med 2003; 1:22-36.
  • Ancoli-Israel S, Palmer BW, Cooke JR, Corey-Bloom J, Fiorentino L, Natarajan L et al. Cognitive effects of treating obstructive sleep apnea in Alzheimer’s disease: a randomized controlled study.J Am Geriatr Soc. 2008;56:2076-81.
  • Ayalon L, Ancoli-Israel S, Stepnowsky C, Marler M, Palmer BW, Liu L, et al. Adherence to Continuous Positive Airway Pressure Treatment in Patients with Alzheimer Disease and Obstructive Sleep Apnea. Am J Geriatr Psychiatry 2006;14:176-80.
  • Benloucif S, Orbeta L, Ortiz R, Janssen I, Finkel SI, Bleiberg J et al. Morning or evening activity improves neuropsychological performance and subjective sleep quality in older adults. Sleep. 2004; 27:1542–51.
  • Bermejo-Pareja F, Benito Leon J, Vega S, Medrano MJ, Román GC; Neurological Disorders in Central Spain (NEDICES) Study Group. Incidence and subtypes of dementia in three elderly populations of central J Neurol Sci. 2008;264:63-72.
  • Bliwise DL. Sleep in normal aging and dementia. Sleep 1993; 16:40-81.
  • Bliwise DL. Normal Aging. Forth ed. Philadephia, PA: WB Saunders Company 2005; 34-28
  • Bombois S, Derambure P, Pasquier F, Monaca C. Sleep disorders in aging and dementia. J Nutr Health Aging 2010;14:212–7.
  • Born J, Rasch B, Gais S. Sleep to remember. Neuroscientist 2006;12:410-24.
  • Brown BM, Rainey-Smith SR, Villemagne VL, Weinborn M, Bucks RS, Sohrabi HR, et al. The relationship between sleep quality and brain amyloid burden. Sleep 2016; 39:1063-8.
  • Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry res 1989;28:193–213.
  • Camargos EF, Louzada LL, Quintas JL, Naves JO, Louzada FM, Nóbrega OT. Trazodone improves sleep parameters in Alzheimer disease patients: a randomized, double-blind and placebo-controlled study. Am Assoc Geria Psych 2014;22:1565-74.
  • Canevelli M, Valletta M, Trebbastoni A, Sarli G, D’Antonio F, Tariciotti L, et al. Sundowning in dementia: Clinical relevance, pathophysiological determinants, and therapeutic approaches. Front Med 2016;3:73.
  • Cardinali DP, Furio AM, Brusco LI. Clinical aspects of melatonin intervention in Alzheimer’s disease progression. Curr Neuropharmacol 2010; 8:218-27.
  • Carvalho DZ, St Louis EK, Knopman DS, Boeve BF, Lowe VJ, Roberts RO, et al. Association of excessive daytime sleepiness with longitudinal β-amyloid accumulation in elderly persons without dementia. JAMA Neurol 2018; doi: 10.1001/jamaneurol.2018.0049.
  • Chibnik LB, Wolters FJ, Bäckman K, Beiser A, Berr C, Bis JC, et al. Trends in the incidence of dementia: design and methods in the Alzheimer Cohorts Consortium. Eur J Epidemiol 2017; 32:931-8.
  • Chong MS, Ayalon L, Marler M, Loredo JS, Corey-Bloom J, Palmer BW, et al. Continuous positive airway pressure reduces subjective daytime sleepiness in patients with mild to moderate Alzheimer’s disease with sleep disordered breathing. J Am Geriatr Soc. 2006;54:777-8.
  • Closser MH. Benzodiazepines and the elderly. A review of potential problems. J Subst Abuse Treat. 1991; 81:35-41.
  • Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 2009;66: 300–5.
  • Elcombe EL, Lagopoulos J, Duffy SL, Leschziner GD, Morrell MJ, Hsiung GY et al. Hippocampal volume in older adults at risk of cognitive decline: the role of sleep, vascular risk, and depression. J Alzheimers Dis 2015; 44:1279-90.
  • Emamian F, Khazaie H, Tahmasian M, Leschziner GD, Morrell MJ, Hsiung GI, et al. The association between obstructive sleep apnea and Alzheimer’s disease: A meta-analysis perspective. Front Aging Neurosci 2016;8:78.
  • Fang H, Zhang LF, Meng FT, Du X, Zhou JN. Acute hypoxia promote the phosporilation of tau via ERK pathway. Neurosci Lett 2010; 414:173-7.
  • Ferini-Strambi L, Marelli S, Galbiani A, Castronovo C. Effects of continuous positive airway pressure on cognition and neuroimaging data in sleep apnea. Int J Psychophysiol 2013; 89:203-12
  • Gaig C, Iranzo A, Pujol M, Perez H, Santamaria J. Periodic limb movements during sleep mimicking REM sleep behavior disorder: A new form of periodic limb movement disorder. Sleep 2017; 40: https://doi.org/10.1093/sleep/zsw063
  • Gaugler JE, Edwards AB, Femia EE, Zarit SH, Stephens MA, Towsend A,  et al. Predictors of institutionalization of cognitively impaired elders: family help and the timing of placement. J Gerontol B Psychol Sci Soc Sci. 2000;55:247-55.
  • Gottesman RF, Schneider AL, Zhou Y, Coresh J, Green E, Gupta N, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017;317: 1443–50.
  • Griffith CM. Obstructive sleep apnea and the risk of Alzheimer’s disease: A systematic review of studies published in the past 10 years. Sleep 2017; 4 (suppl 1):A430.
  • Grothe M, Heinsen H, Teipel SJ. Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiatry 2012; 71:805-12
  • Haba-Rubio J, Marti-Soler H, Marques-Vidal P, Tobback N, Andries D, Preisig M. et al. Prevalence and determinants of periodic limb movements in the general population. Ann Neurol 2016; 464-74.
  • Hatfield CF, Herbert J, van Someren EJ, Hodges JR, Hastings MH. Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer’s dementia. Brain 2004;127:1061-74.
  • Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior disorder. Sleep 2005; 28:203-6.
  • Jaussent I, Bouyer J, Ancelin ML, Berr C, Foubert-Samier A, Ritchie K, et al. Excessive sleepiness is predictive of cognitive decline in the elderly. Sleep 2012; 35:1201-7.
  • Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991; 14:540–5.
  • Ju YS, Mc Leland JS, Tiedebusch CD, Xiong D, Fagan AM, Duntley SP, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol 2013; 70:587-93.
  • Karni A, Tanne D, Rubenstein BS, Askenasy JJ, Sagi D. Dependence on REM sleep of overnight improvement of a perceptual skill. Science 1994; 265:679-82.
  • Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62: 1556–60.
  • Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of sleep-disordered breathing with cognitive function and risk of cognitive impairment: A systematic review and meta-analysis. JAMA Neurol. 2017;74:1237-45.
  • Liguori C, Romigi A, Nuccetelli M, Zannino S, Sancesario G, Martorana A, et al. Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol 2014; 71:1498-1505
  • López-Pousa S, Vilalta-Franch J, Llinàs-Regla J, Garre-Olmo J, Román GC. Incidence of dementia in a rural community in Spain: the Girona cohort study. Neuroepidemiology 2004;23:170-7.
  • Mander BA, Winer JR, Walker MP. Sleep and Human Aging. Neuron 2017; 94: 19-21
  • McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database of Systematic Rewiews 2016; Issue 11.
  • McCurry SM, Logston RG, Teri L, et al. Characteristics of sleep disturbance in community-dwelling Alzheimer’s disease patients. J Geriatr Psychiatry Neurol 1999; 12:53-9.
  • Miller MA, Wright H, Ji C, Cappuccio FP. Cross-sectional study of sleep quantity and quality and amnestic and non-amnestic cognitive function in an ageing population: the english longitudinal study of ageing (ELSA). PLoS One 2014; 9(6):e100991.
  • Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement 2013;9:63–75.
  • Prince M. 2015. World Alzheimer Report 2015: The Global Impact of Dementia http://www.alz.co.uk/research/world-report-2015.
  • Reynolds CF 3rd, Kupfer DJ, Taska LS, Hoch CC, Sewicth DE, Restifo K et al. Sleep apnea in Alzheimer’s dementia: correlation with mental deterioration, J Clin Psychiatry 1985; 46:257-61.
  • Richards KC, Lambert C, Beck CK, Bliwise DL, Evans WJ, Kalra GK et al. Strength training, walking, and social activity improve sleep in nursing home and assisted living residents: randomized controlled trial. Journal of the American Geriatrics Society. 2011;59:214–23.
  • Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 2008; 299:2642-55
  • Rongve A, Boeve BF, Aasland D. Frequency and correlates of caregiver-reported sleep disturbances in a sample of persons with early dementia. J Am Geriatr Soc 2010; 58:480-6.
  • Rose KM, Beck C, Tsai PF, Liem PH, Davila DG, Kleban M et al. Sleep disturbances and nocturnal agitation behaviors in older adults with dementia. Sleep 2011; 34:779-86.
  • Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M et al; Alzheimer’s Disease Cooperative Study. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 2003; 893-901.
  • Skeene DJ, Swadi DF. Melatonin rhythmicity: effect of age and Alzheimer’s disease. Exp Gerontol 2003;38:199-206.
  • Spiegel R, Herzog A, Koberle S. Polygraphic sleep criteria as predictors of successful aging: an exploratory longitudinal study. Biol Psychiatry 1999; 45: 435-42.
  • Spira AP, Gamaldo AA, An Y, Wu MN, Simonsick EM, Bilgel M, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013;70:1537-43
  • Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res 1985; 342:37-44
  • Theofilas P, Ehrenberg AJ, Dunlop S, Di Lorenzo Alho AT, Nguy A, Leite REP, et al. Locus coeruleus volume and cell population changes during Alzheimer’s disease progression: a stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement. 2017; 13:236-46.
  • Tractenberg RE, Singer CM, Cummings JL, Thal LJ. The sleep disorders inventory: and instrument for studies of sleep disturbance in persons with Alzheimer’s Disease. J Sleep Res 2003; 12:331-7.
  • Tranah GJ, Blackwell T, Stone KL, Ancoli-Israel S, Paudel ML, Ensrud KE et al.; SOF Research Group. Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann Neurol 2011; 70:722-32.
  • Troussiere AC, Charley CM, Salleron J, Richard F, Delbeuk X, Derambure P, et al. Treatment of sleep apnoea syndrome decreases cognitive decline in patients with Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2014;85:1405-8.
  • Tsapatou A, Gu Y, Manly J, Schupf N, Tang MX, Zimmerman M, et al. Daytime sleepiness and sleep inadequacy as risk factor for dementia. Dement Geriatr Cogn Dis Extra 2015; 5:286-95.
  • Spiegel R, Herzog A, Koberle S. Polygraphic sleep criteria as predictors of succesful aging: an exploratory longitudinal study. Biol Psychiatry 1999; 45: 435-42.
  • Videnovic A, Lazar AS, Barker RA. ‘The clocks that time us’ circadian rhythms in neurodegenerative disorders. Nat Rev Neurol 2014;10:683-93.
  • Viñuela-Fernández C, Olazarán J. Criterios para el diagnóstico del síndrome de demencia. Guía oficial para la práctica clínica en Demencias: conceptos, criterios y recomendaciones 2009. Editores: José Luis Molinuevo y Jordi Peña-Casanova.
  • Weaver TE, Chasens ER. Continuous positive airway pressure treatment for sleep apnea in older adults. Sleep Med Rev 2007;11:99-111.
  • Winblad B, Amouyel P, Andrieu S, Ballard C, Brayne C, Brodaty H, et al. Defeating Alzheimer’s disease and other dementias: A priority for European science and society. Lancet Neurol 2016;15:455–532.
  • Wu YH, Zhou JN, Van Heerikhuize J, Jockers R, Swaab DF. Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiol Aging 2007; 28: 1239-47
  • Yaffe K, Laffan AM, Harrison SL, Redline S, Spira AP, Ensrud KE, et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011;306:613-9.
  • Yu YS, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013; 70:587-93.
  • Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF. Early neurophathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 2003;35:125-30.