Prevalence

In the DS population, OSA is estimated to occur in 30%–50% of children [25, 26] and upward of 78%–90% in adults with DS based on informant report [27] and objective measures [12, 28, 29]. In adults with DS, OSA has been found to frequently involve significant hypoxemia [12]. Based on their review of literature, Lal et al. [30] outlined the most common manifestations of OSA in adults with DS. In terms of cardiovascular functioning, adults with DS with OSA may present with arrhythmias, congestive heart failure, pulmonary hypertension, and cerebral vascular accident [31, 32]. Neurocognitive and behavioral impairments associated with OSA in adults with DS have been reported to include excessive daytime sleepiness, deficits in executive functioning (e.g., difficulties inhibiting responses and slow processing speed), impaired attention (e.g., difficulties directing and sustaining attention), decreased memory, difficulties regulating behavior and mood, and depressive symptoms [14, 33]. Other reported manifestations of OSA in adults with DS include snoring, nocturia (i.e., waking up during the night to urinate), restless sleep, early morning headache, fatigue, gastroesophageal reflux, polycythemia, and hypercapnia [30].

The reported prevalence of diagnosed OSA based on caregiver-report in adults with DS is often markedly below the 78%–90% prevalence found in studies using observational methods such as polysomnography [11, 12, 29]. For example in a sample of 47 adults with DS aged 26–56 years, only 17 (36%) were reported by caregivers to have OSA, and only 10 of these adults with DS were being actively treated for OSA [34]. This discrepancy suggests that OSA often goes undetected, and subsequently untreated, in adults with DS. There is similar evidence that OSA often goes undetected in children with DS, as a marked discrepancy between caregiver-report of OSA concerns and objective measures of OSA has been reported. For example in a study of 56 children with DS [35], 69% of parents reported no sleep problems in their child with DS, yet 54% of these children with DS evidenced OSA based on polysomnography. Moreover, of the parents who reported sleep problems in their child with DS, only 36% had abnormal sleep results on polysomnography.

The detection of OSA in both children and adults with DS may be difficult because the manifestations of OSA overlap with conditions that are highly comorbid in DS. For example, both DS and OSA involve impairments in memory, attention, and executive functioning. Similarly, both DS and OSA are comorbid with cardiovascular disease, hypothyroidism, and obesity, and involve fatigue, daytime sleepiness, as well as impairments in neurocognitive functioning. In addition, children and adults with DS may not always be able to accurately report problems with sleep, and caregivers are not necessarily able to observe these problems. Barriers to detecting OSA in adults with DS also include lack of access to sleep clinics, and lack of access to sleep specialists with experience supporting individuals with DS. In addition, many adults with DS may not tolerate clinic-based sleep studies that require an overnight visit and polysomnography.

Risk factors and comorbid conditions

The elevated prevalence of OSA in DS is thought to be related to a predisposition toward upper airway obstruction (see Fig. 1). Individuals with DS evidence midface and maxillary hypoplasia, which reduces airway dimensions [36, 37]. Indeed, MRI studies have revealed airway obstruction from macroglossia and hypotonia, and resulting glossoptosis and hypopharyngeal collapse [38]. Subglottic and tracheal stenosis is more frequent in individuals with DS relative to those without DS [39, 40]. Lingual tonsillar hypertrophy, which is markedly elevated in children with DS who have OSA relative to children without DS who have OSA [41], can also add to airway obstruction. Laryngomalacia has been found to occur in 50% of children with DS indicating that hypotonia at the supraglottic level also occurs and may contribute to the heightened risk for OSA in DS [42].

The elevated prevalence of OSA in adults with DS may also be associated with obesity. Across studies, between 45%–79% of males and 56%–96% of females with DS are reported to be overweight [43–46]. The deposition of fat in the lateral wall of pharynx can contribute to the airway obstruction. In addition, central adiposity, defined as the accumulation of fat in the lower torso around the abdominal area, has also been associated with OSA [47, 48]. Adults with DS have a heightened risk for central adiposity [49]. In studies of adults with DS, obesity has been shown to be related to increased risk for OSA [11, 29, 50, 51], and a higher AHI [12]. However, not all studies have reported an association between obesity and OSA in DS samples [51–53], suggesting that further research is needed to understand if obesity is only a risk factor for OSA at certain life stages (e.g., in adulthood but not in childhood) and/or if other comorbid conditions and risk factors often overshadow the contribution of obesity to OSA in DS.

Individuals with DS also have an increased risk for gastroesophageal reflux [54], which can contribute to obstruction of the airway due to inflammation of the esophagus. Hypothyroidism has also been posited to contribute to risk of OSA. Studies indicate that approximately 10% of children with DS have congenital or acquired thyroid disease, with prevalence increasing to 13%–50% in adulthood [55, 56]. Hypothyroidism has been associated with increased risk for OSA [57, 58] potentially because of narrowing of the pharynx because of soft tissue infiltration by mucopolysaccharides and proteins and/or loss of control for the pharyngeal dilator muscles [56].

Treatment implications

Given the high risk for OSA with aging, established healthcare guidelines established by the National Down Syndrome Society (NDDS; https://www.ndss.org/resources/healthcare-guidelines/) and Global Down Syndrome Foundation (https://www.globaldownsyndrome.org/medical-care-guidelines/) and other professional DS organizations recommend regular screening for OSA in adults with DS. This is particularly true for adults with DS who evidence medical conditions that may increase risk for OSA and/or be manifestations of OSA, such as obesity, gastroesophageal reflux, hypothyroidism, and cardiovascular disease. Screening should include objective measures such as polysomnography or devices using peripheral arterial tone signaling, as self- and caregiver-report may not be sufficient to accurately detect sleep distributions in adults with DS.

Treatment of OSA is based on the severity of the condition and contributing factors. For example, treatment aimed at weight loss (e.g., dietary restrictions and physical exercise) may be relevant when obesity is a contributing factor to OSA. Management of thyroid levels should be targeted when hypothyroidism is present. Nasal decongestants and allergy medications may be used for snoring and mild cases of OSA. In addition, strategies for altering body position at night to increase airflow such as avoiding sleeping on one’s back, pillows, or reclining beds may be part of treatment recommendations.

For some adults with DS, dental appliances (e.g., tongue-retaining devices) may be an option for increasing airflow. However, in non-DS populations, the use of dental appliances has been shown to be less effective in treating OSA than positive airway pressure [59]. Researchers have argued that dental appliances may be ineffective for treating OSA in adults with DS given the multitude of factors that contribute to upper airway obstruction in DS [30]. Adults with DS may also have low tolerance for wearing these devices at night.

Among the most common treatments for OSA is positive airway pressure, which can be applied as continuous positive airway pressure (CPAP) or bilevel positive airway (BPAP). Although there are limited studies evaluating the efficacy of positive airway pressure in adults with DS, preliminary evidence supports the efficacy of CPAP in improving sleep and associated characteristics, including cognitive functioning (attention and executive functioning) and emotional/behavioral symptoms [60].

There is evidence that compliance with OSA treatment, and especially positive airway pressure devices, is low in both children and adults with DS. In a Wisconsin cohort of 47 adults of DS aged 26–56 years [34], who are part of the Alzheimer’s Biomarkers Consortium—Down Syndrome (https://www.nia.nih.gov/research/abc-ds), only 10 of the 17 adults with DS diagnosed with OSA used recommended CPAP or BPAP devices, and this reported to be only partial compliance (i.e., did not use device as often as recommended and/or for as long as was recommended during the night) in 6 adults with DS. This level of CPAP or BPAP compliance (i.e., 4 of 17 [24%] fully complied) is at the low end of range in compliance (25%–50%) reported for adults with OSA who do not have DS [61, 62]. Thus not only is it likely that OSA is often underdiagnosed in adults with DS, but when diagnosed, this condition is often not adequately treated. It may be possible to increase compliance with PAP device by pairing this treatment with desensitization strategies, cognitive-behavioral therapy, and/or psychoeducational strategies that can teach caregivers and adults about the benefits of using the device and adjusting to wearing the device at night.

The Food and Drug Administration recently approved the use of hypoglossal nerve stimulation for individuals with moderate to severe OSA who cannot tolerate CPAP, which extends to adults with DS [61]. The hypoglossal nerve stimulator is an implanted device that reduces OSA by electrically stimulating the hypoglossal nerve to the tongue. The devices are currently being tested for use with children with DS and OSA that have not tolerated CPAP. Recent studies have shown promising results in children with DS, with the device being well tolerated and moderate-sized reductions in OSA severity (e.g., 85% reduction in AHI) following implantation of the device [62].

Surgical treatments that alter the upper airway may also be considered such as septoplasty turbinate reduction, adenotonsillectomy, uvulopalatopharyngoplasty, lingual tonsillectomy, and maxillary and/or mandibular surgery. However, ongoing monitoring of sleep postsurgery is warranted as children with DS have continued to require other interventions, including PAP or surgical revisions [35]. In instances of persistent severe OSA not amenable to other treatment, tracheostomy may be necessary.

Sleep onset, length, and awakenings

These problems include caregiver-reported difficulties with sleep initiation or onset, difficulties with sleep maintenance, and early wakening.

More recent studies of adults with DS have used objective measures of sleep initiation and maintenance such as polysomnography and wrist-worn actigraph. Actigraphy is a noninvasive method of assessing continuous activity including information on sleep/wake states through an accelerometer. The device is typically worn on waist or wrist. These studies indicate disturbances in sleep onset or maintenance are markedly underreported when using self- and parent or caregiver-reports relative to objective measures [29, 34]. In a sample of 54 adults with DS (mean age of 39 years, range 20–62 years), Gimenez et al. [29] conducted polysomnography across two nights and assessed sleep quality using wrist-worn actigraph for seven consecutive nights. Polysomnography and actigraphy indicated that about 75% of adults with DS evidenced poor sleep efficiency, defined as sleep efficiency of less than 85% which is generally considered minimum adequate sleep efficiency. On average, adults with DS in the Gimenez et al. [29] study evidenced 103–126 min of wake after sleep onset (WASO) per night and a total sleep time of 340–384 min (5.7–6.4 h) based on polysomnography and actigraphy indices, respectively. This total sleep efficiency, total sleep time, and WASO were significantly lower than that of a comparison group of adults without DS who were matched on biological sex, chronological age, and body mass index. These findings are similar to that reported by Cody and colleagues [34] in a different sample of 47 adults with DS (mean age of 38 years, range 26–56 years). In the Cody et al. [34] study, participants also wore wrist-worn actigraph for seven consecutive nights. Consistent with findings of Gimenez et al. [29], in the Cody et al. [34] study adults with DS had an average WASO of 113 min per night, total sleep time of 6.8 h per night, and mean sleep efficiency of 75% per night (SD = 7.6%), indicating that sleep disturbances are both common and severe in adults with DS. While sleep has been shown to become more fragmented with age in the general population, the earlier mentioned studies [29, 34] suggest that these age-related effects occur at an earlier age and with more severity in the DS population relative to the general population.

Sleep stages and circadian rhythm

Normative sleep has a cyclical pattern that involves shifts between the sleep stages, and includes nonrapid eye movement and rapid eye movement (REM) sleep. Non-REM sleep involves synchronous cortical electroencephalogram (EEG), including sleep spindles, K-complexes, and slow waves, and dreaming is rare. In contrast, REM sleep EEG is desynchronized, muscles are atonic, and dreaming often occurs (for review, see Ref. [65]). In adults, the typical pattern is that sleep begins in non-REM and progresses through deeper non-REM stages (stages 2, 3, and 4 or stages N2 and N3) and with the first episode of REM sleep occurring about 80–100 min after sleep onset. Generally, REM stages 3 and 4 (or stage N3) occur in the early non-REM cycles, and REM sleep episodes lengthen across the night.

In adulthood in the general population, age-related changes occur in both sleep stages and cycles as well as in circadian rhythms. With aging, individuals often have more difficulty falling sleep and awaken more often in the night. Slow-wave sleep (stages 3 and 4) slowly declines across adulthood, with older adulthood associated with fewer and shorter episodes of slow-wave sleep and REM sleep. Older adults appear to be more easily aroused from sleep and often awaken multiple times during the night. These aging effects tend to be more pronounced in men than in women [66]. Across studies, the prevalence of sleep disorders also tends to increase with age across adulthood. In part, increases in sleep disruptions may be linked to age-related physical conditions or mental health conditions and side effects of medications for these conditions [66]. Age-related changes in circadian rhythms have also been found, including a tendency to become sleepier in the early evening and wake earlier in the morning compared to younger adults [66].

Although much less studied, there is some evidence that sleep cycles and circadian rhythms are also commonly altered in adults with DS. Using polysomnography, Gimenez et al. [29] found that relative to the comparison group of adults without DS, adults those with DS evidenced an increased percentage of stage N1 and N3 sleep and decreased percentage of REM sleep. Nearly all adults with DS had less than 20% REM sleep. Men with DS had a higher percentage of stage N1 sleep than women with DS.

Problems with sleep initiation and maintenance appear to have marked effects on the cognitive functioning of both children and adults with DS. A low total sleep time and fragmented sleep, as assessed through both caregiver-report and objective measures, has been found to be associated with poorer learning and language ability in children with DS [67]. A longer length of nighttime awakenings via actigraph was found to be associated with worse performance on directly administered measures of episodic memory, executive functioning, and motor planning and coordination in adults with DS [34].

Behavioral sleep problems or sleep-related movement disorders

Findings on other types of abnormal sleep behaviors and sleep-related movement disorders in adults with DS have received less research attention and primarily been assessed by caregiver-report. Among the most common problems reported in a sample of 100 caregivers of adults with DS aged 16–61 years were teeth grinding during sleep (39%) and sleep talking (26%), as well as behaviors associated with OSA including breathes through mouth (84%), snores loudly (53%), and difficulty breathing during sleep (33%). Few concerns for nightmares or night terrors were reported [50]. Problems with daytime sleepiness were also reported with the most common being lacks energy during the day (45%), and excessively sleepy during the day (38%), irritable during the day (33%). Across studies, behavioral sleep problems were found to be associated with higher rates of epilepsy/seizures and musculoskeletal problems [50]. Adults with DS with abnormal sleep behaviors are reported to be older than adults with DS without reported sleep problems [64]. There were no differences in prevalence of caregiver-reported abnormal sleep behaviors or problems with sleep initiation or maintenance by level of intellectual disability [50].

Using observation and objective measures (polysomnography and actigraph), Gimenez et al. [29] reported sleep talking in 43% of their sample of adults with DS (generally in non-REM stages) and periodic limb movements in 21% of the sample. There were no incidences of non-REM movement-related parasomnia, no sleepwalking, REM sleep behavior disorder, epileptic seizures, and no evidence indicative of restless leg syndrome.

Treatment implications

Challenges with sleep onset and maintenance are often treated with medication, both for children and adults with DS and in the general population [68]. However, to date, little research has examined the effectiveness of these medications in the DS population. Very few children or adults with DS are noted to seek out behavioral strategies to address sleep disturbances or problems beyond OSA. Yet, emerging evidence suggests that behavioral strategies may be effective in supporting sleep hygiene in children with DS [68] and many of these same strategies could be applied to adults with DS.

Next steps in research

Going forward, there is a need for research to evaluate the efficacy of medications to reduce difficulties falling and remaining asleep, as well as abnormal sleep behaviors in adults with DS. Currently, there is a paucity of information regarding the best medication options, dosages, and medication metabolism rates given physiological differences in DS. It will also be important for research to better understand the side effects of these medications and their potential long-term impact on other aging processes in DS. Given concerns about medication side effects and/or adverse interactions with other medications that adults with DS may be taking as they age (e.g., thyroid hormone replacements for hypothyroidism, allopurinol for gout, aripiprazole for behavior management, cholinesterase inhibitors for dementia), it will be important for research to also evaluate the efficacy of behavioral strategies for managing sleep disruptions in adults with DS. For example, research is needed to identify ways to tailor current behavioral therapy or psychoeducational strategies that have been developed for the typically developing population for adults with DS. These strategies may include efforts to help adults with DS develop consistent sleep schedules, establish relaxing bedtime routines, limit bright lights or screen time before bed, and avoid the intake of foods and drinks (e.g., chocolate, caffeinated beverages, overall fluid intake) later on in the day that may impact sleep.

In the general population, the aging-related increase in problems falling and remaining asleep, as well as abnormal sleep behaviors and sleep-related movement disorders, are more pronounced in men than in women [66]. Recent evidence [29] suggests that this may also be true in adults with DS; however, this is also an area in need of further research. It will also be important for the field to understand the possible connections between sleep disruptions and other comorbid medical conditions that are frequently experienced in DS, as these connections may offer important insight into underlying biological mechanisms that could be the target of treatment.

Treatment implications

Understanding the association between sleep and AD, and the pathophysiological mechanisms driving this association, has important implications for the development of intervention for delaying or preventing the onset of AD in the DS population. There are established and efficacious treatments for many types of sleep disruption. If future research finds that disrupted sleep plays a role in driving or exacerbating the effects of AD pathophysiology, then sleep treatments could offer a way to potentially slowing down AD progression.

Next steps in research

Moving forward, it will be important for longitudinal research to examine other aspects of sleep and other aspects of early AD pathophysiology (e.g., tau, inflammation, white matter integrity, cortical thickness—see Chapters 2, 3 and 8), in addition to β-amyloid in the DS population, to better clarify the mechanisms driving this connection between sleep and AD. For example, OSA has been associated with increased β-amyloid in the general population [92]. Given estimates that upward of 90% of adults with DS have OSA [12], it will be important for future research to understand the role of OSA in potentially accelerating the accumulation of β-amyloid and/or other aspects of psychopathology and/or the effect of this pathophysiology on the transition to clinical AD. For example, oxidative stress has been proposed to play a role in the pathophysiological DS [93] and is also impacted in OSA following hypoxemia [94].

Other aspects of sleep assessed should be the focus of future research examining the role of sleep in the early AD in DS including altered REM sleep and altered patterns of circadian sleep-wake rhythms, as both have been associated with AD pathophysiology in non-DS populations including β-amyloid, but also inflammation and cerebral blood flow [95, 96].