Clinical manifestations

Presentation and course

Sleep changes in aging persons. Sleep clearly changes with aging (27; 23; 59).

Along normal aging the macrostructure of sleep changes. Sleep duration, total sleep time, sleep efficiency, slow wave sleep, and REM sleep decrease whereas the number of awakenings and the duration of time awake during the night increase, as described in a large meta-analysis from 65 studies (polysomnography - actigraphy) on 3577 healthy persons between 5 and 102 years of age (78). Two meta-analyses confirmed a linear decrease of total sleep time with aging (10-12 minutes per decade), but this reduction was not clearly detected after 60 years of age, indicating a plateau in this period of life (31). A laboratory study on 50 healthy adults between 19 and 81 years of age demonstrated that, considering spontaneous sleep over the 24 hours, older adults had significantly reduced nighttime sleep duration (8.1 hours) as compared to middle-aged (9.1 hours) and young (10.5 hours) adults (15).

Sleep initiation, the ability to reinitiate sleep after nocturnal awakenings, and sleep maintenance remain substantially unchanged after the age of 60 years. Conversely, a slow decline in sleep efficiency has been detected with advancing age (78; 27).

In general, in healthy aging, slow wave and REM sleep decrease while stage 1 and stage 2 increase but without significant differences as compared to young adults. Also, the reduction in REM sleep latency has not demonstrated significant changes: a linear, only 0.6% per decade decrease has been observed until 75 years of age whereas a small increase was found between 75 and 85 years (31). Often, REM sleep alterations only emerge as a symptom of degenerative dementias (61; 14). Even the microstructure of sleep, including the quality and quantity of sleep oscillations (micro arousals), changes with aging (68).

It is not always easy to define a complete health status in the elderly considering also the possibility of preclinical and prodromal phases of neurodegenerative disorders, Alzheimer disease in particular (46).

A worse health status is often attributable to an increase in chronic conditions, cognitive decline, and medication use, which can precipitate insomnia or excessive daytime sleepiness.

In the National Sleep Foundation’s 2003 poll 71% of those who rated their health status as fair-to-poor reported insomnia and 29% reported drowsiness. The Established Populations for Epidemiologic Studies of the Elderly found a self-reported fair-to-poor health status in 36% of community-dwelling persons aged 65 years or older and it was significantly associated with insomnia symptoms (34).

A relevant topic has not yet been completely elucidated: do older persons sleep less simply because they need less sleep, or do they need more sleep than that they can generate?

In a 2007 paper Fragoso and Gill supported that “senescence in the form of usual aging is characterized by a reduction in health status, loss of physical function, and primary sleep disorders, all of which are capable of precipitating sleep complaints and adverse outcomes.” The authors consider sleep complaints as a consequence of multiple and interdependent predisposing (reduced sleep spindles, slow wave sleep, REM sleep, and advanced phase of sleep), precipitating (reduced health status, loss of physical functions, primary sleep disorders), and perpetuating factors (social isolation, loneliness, inactivity, inadequate sleep hygiene, caregiving, bereavement) (34).

Other authors have mainly supported the hypothesis that sleep complaints in older persons are not related to the aging process “per se,” emphasizing the importance of comorbidities and primary sleep disorders (32; 02).

In an exhaustive review on sleep and human aging, it is possible to find all major studies in favor or against the two hypotheses (68). Some scientific evidence supports that sleep need is reduced in the elderly who show less intense "rebound” sleep and a minor reduction of attention after deprivation, and less subjective sleepiness with sleep restriction. Other authors argue that sleep need is not significantly changed while sleep-generating ability is impaired. Currently, no clear consensus exists, but the evidence seems to be slightly in favor of the hypothesis that older adults have an alteration in their ability to register, perceive, or generate the sleep they need (68).

Chronic conditions show a high prevalence in older adults. According to the National Sleep Foundation’s 2003 poll, 43% of involved persons reported two to three chronic conditions, 24% four or more, and only 10% reported none. The most prevalent conditions were hypertension (47%), arthritis (46%), enlarged prostate (22% of men), heart disease (18%), depression (16%), and diabetes (15%). Nocturia and related sleep disturbance were present in 65% of men and women. Other epidemiological studies and several papers confirmed these data. Each of these disturbances can cause sleep disorders.

On the other hand, a 2020 Swedish national ongoing population-based study with a 9-year follow-up demonstrated that moderate to severe sleep disturbances are associated with a higher speed of accumulating chronic disease, particularly musculoskeletal and neuropsychiatric disorders (94). The study emphasizes the importance of early detection and treatment of sleep disorders to possibly reduce chronic multimorbidity connected with aging.

Several sleep disturbances are highly prevalent in older adults and patients with dementia (02; 76; 43):

	• Insomnia
	• Sleep disordered breathing (obstructive sleep apnea in particular)
	• Restless legs syndrome
	• Periodic limb movements
	• Rapid eye movement sleep parasomnias (REM sleep behavior disorder in particular)
	• Excessive daytime sleepiness

The Hypnolaus study on 3043 participants (age range: 40 to 85 years; 48% men) found a prevalence of moderate-severe obstructive sleep apnea in 23.4% of women and 49.7% of men: the prevalence increased from 60 years and over (48). REM sleep behavior disorder can precede a synucleinopathy by decades and has been introduced as a core criterion for the diagnosis of Lewy body dementia (70).

Hypertension, diabetes, and heart disease are often associated with sleep-disordered breathing and depression is associated with insomnia. Hypertension, arthritis, depression, and diabetes mellitus are associated with sleep-related movement disorders such as restless legs syndrome. In the National Sleep Foundation’s 2003 poll, self-reported snoring, apnea, insomnia, and restless legs syndrome rose with the increase in the number of chronic conditions (102).

A retrospective, cross-sectional study on the clinical characteristics of sleep apnea in 102 geriatric inpatients confirmed that excessive daytime sleepiness and comorbidities burden were independently associated with a polygraphic obstructive sleep apnea diagnosis, emphasizing the importance of always suspecting obstructive sleep apnea in comorbid, sleepy older patients (74).

Medication use in the elderly is high and a relevant contribution to the high number of medications used can be attributed to sleep disorders. In 2002, 44% of United States community-living older persons reported taking 5 or more medications a week, also including herbal/supplements, vitamins, and minerals (54).

In the National Sleep Foundation’s 2003 poll, 20% of participants used hypnotics at least a few nights a week. In the National Follow-Up Survey of Self-Care and Aging, 48.1% of persons used a large number of medicines for arthritis, most often to improve sleep disruption related to pain (32).

A 2020 systematic review investigated the relationship between sleep complaints and frailty among older adults (106). Six cross‐sectional studies and one longitudinal study were considered and demonstrated consistent evidence of the association between subjective sleep quality and frailty. Data on insomnia symptoms, excessive daytime sleepiness, and sleep-wake pattern were inconclusive: the authors underlined that more studies with validated instruments are needed regarding these topics. On the other hand, insomnia and excessive daytime sleepiness seem to predict 20-year mortality in older adult males, as demonstrated by an Italian study conducted in the city of Udine on 750 subjects aged 65 years and older (71). Risk was determined to be independent of cancer, depression, dementia, cardiovascular diseases, and the use of sleeping pills. Moreover, excessive daytime sleepiness was associated with increased malnutrition, dysphagia, and vitamin D deficiency, regardless of age, gender, living status, polypharmacy, dementia, insomnia, and ischemic heart disease. The relationship seems to be bidirectional and emphasizes the benefit of assessing and treating excessive daytime sleepiness in malnutrition (56). Another study demonstrated that excessive daytime sleepiness was associated with an increased number of falls and sarcopenia in a sample of 575 older adults (95).

In older adults, sleep seems to be more sensitive to the circadian timing and circadian sleep-wake rhythm disorders. Persons with preclinical and clinical cognitive decline show relevant alterations in circadian sleep-wake rhythms. Sleep disturbances are present in the early phases of dementia and can contribute to a faster and more severe cognitive decline. The prevalence of circadian sleep-wake rhythm disorders in older adults is not completely defined: they are difficult to identify only based on subjective complaints. For instance, early morning awakenings have been detected in 20% to 30% of older adults but when excluding comorbidities such as depression, pain, physical limitations, and respiratory disturbances, only 4% of older adults report early morning awakenings, which are often difficult to differentiate from an advanced sleep phase disturbance in older adults and patients with dementia. The advanced sleep phase disturbance is rare among older persons, but it is more prevalent than in young adults and can be connected to sundowning, which is almost endemic in patients with dementia (105; 41). The delayed sleep-wake phase disorder is rare in older adults. Irregular sleep-wake rhythm disorder is more frequent in patients with dementia and among institutionalized individuals partially due to the lack of environmental and behavioral inputs. Non-24-hour sleep-wake rhythm disorder is rare in older adults but may be a consequence of vision loss. Moreover, older shift workers use more hypnotics for severe sleep disturbances (110; 55). Circadian sleep-wake disorders seem to be connected to sundowning, which is almost endemic in patients with dementia, but also present in nondemented older adults (16). More data on circadian dysfunction are needed in older persons and in patients with dementia using not only behavioral, but also biological, markers to tailor specific therapies.

Excessive daytime sleepiness, sleep deficiency, and their human impact even in older adults. In 2005, a population study considered a random sample of 16,583 men and women from central Pennsylvania between 20 to 100 years of age. The authors found that excessive daytime sleepiness, often linked to cognitive impairment and other sleep and medical disorders, declines between the ages of 30 and 75 years and at a greater rate after 75 years of age (11). However, it is present in the “young old” group of people, still employed, socially active, and driving vehicles, with evident associated risks. A 2021 review on the age-related effects of sleepiness on driving included five articles investigating sleepiness only by self-reported standardized methods, two studies also using a behavioral task, and three studies using objective, EEG recordings (89). The restricted available literature seems to indicate that older drivers are less impaired by sleep loss when driving than young adults, with several discrepancies related to different lifestyles; the elderly are inclined to avoid dangerous driving.

Wittman and colleagues introduced the circadian definition of social jet lag, a misalignment between circadian and social clocks (107): 69% of adults report at least 1 hour of social jet lag. It tends to decline with age but together with shift work disorders it may affect older persons (usually more vulnerable to misalignment of circadian rhythms) to a greater extent acting on age-related sleep changes (88).

The National Sleep Foundation’s 2003 Sleep in America Poll on sleep and aging indicated that older adults aged 55 to 84 years were more regular in their sleep duration in weeknights and weekends (7 and 7.1 hours respectively) as compared to persons aged 18 to 54 (76). According to this survey,13% of older persons sleep less than 6 hours during the week and 11% sleep less than 6 hours during weekends. Moreover, 9% of older adults sleep 9 hours and more during the weekend against 8% during the week.

The overall impression is that since 2003 sleep habits have changed and, probably, analyzing also distinct age subgroups of older persons, sleep data could be different than before: this should be a new tool for the research agenda.

At present, it is difficult to define specific social rhythms for older persons and for women, particularly those whose working and familial rhythms are more interconnected. Moreover, time of retirement is changing, and many retired persons often maintain relevant intellectual, physical, and working activities until 75 years and more, also due to the opportunities given by our digital and interconnected world. To what extent the duration and timing of sleep is altered by work and retirement is not yet well known. Existing data report that people sleep longer and later after retirement, but available studies are mainly based on self-reported evaluations or comparisons between individuals. A study investigated 100 people aged between 61 and 72 years who were retired from paid work using accelerometers, diaries, and questionnaires (39). Measures were repeated after 1 and 2 years. Sleep duration increased by 21 minutes, whereas sleep efficiency remained substantially unchanged. Sleep onset and final awakening were delayed by 26 and 52 minutes, respectively, and midsleep was forwarded from 03:17 to 03:37 hours. Social jetlag decreased but still occurred after retirement.

A cross-sectional study on the association between social jet lag, metabolic syndrome, and type 2 diabetes in the general population found no significant association in older adults whereas it was found in younger adults with more than 1 hour of social jet lag. The authors described a reduced entity of social jet lag in adults above the age of 61 (24%) who had more metabolic syndrome at baseline, emphasizing the role of the longer previous exposition to social jet lag in older persons (57).

Usual sleep duration has substantially decreased since the 1960s, even among older persons who still drive and have high prevalence of obstructive sleep apnea: these conditions are strongly associated with motor vehicle crashes in the general population (42).

Some mathematical models have been proposed to assess sleepiness and these new methods may also be useful for older adults (01). A paper proposed new formulae to combine social jet lag and chrono-disruption concepts to compute sleep deficiency, defined as insufficient quality and quantity of sleep (26).

The clinical definition and detection of excessive daytime sleepiness is particularly challenging in the elderly with related problems in prevalence studies. Excessive daytime sleepiness is often related to medical and primary sleep disorders such as obstructive sleep apnea, circadian sleep-wake rhythm disorder, restless legs syndrome, and, in a minor percentage, central disorders of hypersomnolence. Excessive daytime sleepiness has been identified and confirmed as a risk factor for cognitive decline and dementia in older adults (37; 19). Moreover, excessive daytime sleepiness is an independent risk indicator for cardiovascular events and mortality in the elderly (25).

Drowsiness is most often established by self-reported napping behavior and, less often, by a scale (eg, the Epworth Sleepiness Scale). The latter is a brief self-administered questionnaire with scores ranging from 0 to 24, with higher scores denoting greater drowsiness. The Epworth Sleepiness Scale demonstrated reduced sensitivity and specificity in older persons and in cognitive decline (35); therefore, it should be used cautiously in these populations. Daytime napping can be a routine for many individuals at different stages of the life course and may have cultural influences. Napping may also be performed to compensate for nighttime sleep loss, to recover energy, and to reduce daytime sleepiness. In older adults, the progressive reduction of working and social activities offers more time for naps. Napping has been demonstrated to be more prevalent in older adults. The National Sleep Foundation’s 2003 poll reported 1 or more symptoms of insomnia in 46% of older adults aged 65 to 74 years and 50% among those aged 75 to 84 years, with rates for napping of 39% and 46%, respectively. These data are in accordance with the Established Populations for Epidemiologic Studies of the Elderly study (34). In a Japanese survey, 27.4% of older adults naps frequently (naps for 4 or more days per week) compared to only 14.4% of middle-aged adults. No data demonstrate that nap duration differs between older adults and other age groups (29; 36). According to Yoon and colleagues, older adults tend to nap more in the early evening whereas younger adults nap in the afternoon (108), and this could contribute to the difficulty in identifying advanced sleep phase disturbances in older persons with cognitive decline. Napping is more frequent when associated with excessive daytime sleepiness, depression, pain, and nocturia but these are conditions often present in healthy aging (33; 59). A paper described the napping characteristics and cognitive performance in older adults, subdividing napping habits into 6 different age groups: 65-69, 70-74, 75-79, 80-84, 85-89, and over 90 years to better examine the phenomenon. In United States community-dwelling older adults, frequent, unintentional, and longer naps correlated with worse performance on cognitive tests or self-rated memory. Napping showed utility as a marker of higher risk for neurodegeneration for care and preventing programs (82).

New operational definitions and instruments to assess excessive daytime sleepiness in population studies, particularly in older persons, are necessary to separate social, physiological, and pathological aspects for the best therapeutic and preventive approaches. In 2012, Ohayon and colleagues described and used the Sleep-EVAL, a “knowledge based expert system”, to detect excessive daytime sleepiness in a cohort of 15,929 persons from 15 American states, aged from 18 to 102, with 16.9% retired persons. Excessive daytime sleepiness was more prevalent (27.8%) than previously reported. Individuals aged 55 to 64 and those over 65 years scored 22.9% and 24%, respectively, with significant differences only when compared to those aged 18 to 34. They underlined the importance of deeply and extensively investigating excessive daytime sleepiness using more descriptive dimensions, such as chronicity, severity, comorbidity, and age (79).

The need to distinguish excessive daytime sleepiness “per se”, secondary to primary sleep disorders (circadian sleep-wake rhythm disorder in particular) or related to social and environmental aspects, is crucial in the clinical and therapeutic settings and particularly in neurodegenerative disorders. The association of biomarkers such as melatonin, cortisol, and body core temperature gives new opportunities (55) but more studies are needed.

Aging sleep and hormonal changes. Several hormonal changes have been considered to understand sleep changes in aging.

Growth hormone shows pulsatility during nocturnal sleep, regardless of the phase and fragmentation of sleep. An age-related decrease in growth hormone secretion has been demonstrated and in older adults its decreased secretion seems to parallel slow wave sleep decrease in an unclear manner. No clear evidence demonstrates that the secretion of prolactin alters sleep, but fragmented sleep in healthy older adults can decrease prolactin secretion. Sleep, particularly slow-wave sleep, inhibits cortisol secretion. Among older adults, changes in the circadian cortisol rhythm can be associated with altered circadian patterns and more frequent awakenings during the night.

Thyroid-stimulating hormone secretion follows a circadian pattern with a low level during the day and a peak connected to sleep. This circadian release does not show significant changes with aging, but some studies demonstrate that its total 24 hours secretion is decreased (06).

In aging, 24-hour melatonin secretion decreases but daytime melatonin may remain unaffected, whereas the nocturnal increase is significantly reduced when compared to young adults and the complex associations with sleep are not completely understood. New evidence is expected in the coming years, also from older adults with cognitive decline (90; 59).

Sleep disturbances and sex differences. In 2014, a report from the Society for Women’s Health Research (66) highlighted the importance of considering the role of sex (and gender) differences in sleep and its disturbances at any age. As they get old, women report a subjective worsening of sleep parameters (ie, sleep quality, sleep latency, total sleep time, sleep efficiency) as compared to men (101; 65). However, using objective measures of sleep (ie, actigraphy and polysomnography) older men show shorter and more fragmented sleep with lower slow wave sleep and REM and increased lighter sleep stages as compared to women (100; 101). This discrepancy between self-reported and objective sleep could be partially explained by the evidence that the circadian period, which regulates melatonin production and temperature rhythms, is significantly shorter in women than in men (24; 05). Even if sleep timing appears to be equivalent in the two sexes, women’s circadian times are set earlier than men, leading to a greater predisposition for women to advanced sleep-wake phase disorder and insomnia (110; 40; 55). An advanced circadian phase may be connected to early morning awakening, a common complaint in menopausal women (84).

Perimenopausal, menopausal, and postmenopausal women complain of worse insomnia symptoms, have a higher risk of developing obstructive sleep apnea, and report an increase in restless legs syndrome and sleep-disordered breathing severity (28; 73). Altered estrogen and progesterone levels may impact negatively on the upper airway function with higher incidence of sleep-disordered breathing in post menopause (63). Sleep duration correlates with obesity in children and young adults: data on older persons are less clear but three wide studies in the United States, Finland, and Spain demonstrated a stronger association in older women. Short sleep duration has been demonstrated to be associated with increased risk of hypertension, coronary heart disease, and stroke, with women showing higher vulnerability. Other studies found that longer sleep duration correlated with diabetes and cardiovascular disease risk and mortality, probably through comorbidities. Objective measurements of sleep parameters demonstrated that the interaction of sleep duration and insomnia or poor sleep quality had a higher impact on cardiovascular disease risk without significant differences between men and women. However, studies with objective measurements of sleep in older persons are limited at this time and more prospective studies are needed (17; 98). Obesity is clearly linked to sleep-disordered breathing and in a wide polysomnographic study, sleep-disordered breathing severity determined a higher risk of cardiovascular disease and related mortality in older women as compared with men (85). Even considering all this evidence, a bias in the access to sleep clinics still exists. For example, the prevalence of referrals to a sleep clinic for obstructive sleep apnea is from twice to 3 times higher in men than in women (08; 04). Compared to men with similar obstructive sleep apnea severity, women diagnosed with obstructive sleep apnea are usually older, have higher BMI, and present with more comorbidities (91; 08; 04). Moreover, they report a poorer quality of life associated with obstructive sleep apnea, exacerbated by comorbid insomnia, which is usually the reason why women are more often referred to sleep clinics (91; 99). This suggests an under-recognition of obstructive sleep apnea in women explained by a different obstructive sleep apnea symptoms’ presentation. Although men usually report more snoring, daytime sleepiness, and witnessed apnea, women complain more about fatigue, insomnia, restless legs, depression, morning headaches, and impaired cognition (08; 77; 13).

Prognosis and complications

Untreated sleep disturbances can determine more medication use and contribute to the onset of other chronic conditions. Sleep supports and drives major physiological functions such as immune, metabolic, endocrine, thermoregulatory, and cardiovascular functions (50). Moreover, sleep is involved in motor control, learning and memory, attention, motivation, emotional balance, and decision making. All these functions can be impaired by age-related sleep disturbances. Sleep disorders since middle age can contribute to the pathological preclinical processes of several neurodegenerative disorders, especially Alzheimer disease (68; 64), and they are an independent risk factor for cognitive decline. Sleep and sleep-wake rhythm disturbances need to be managed at an early stage, considering the importance of the timing of risk factors for dementia (72).

Clinical vignette

Fictitious clinical case. A 54-year-old man was referred to a sleep center because of excessive daytime sleepiness (often arising abruptly and exacerbating in the afternoon) and fatigue he had experienced for almost 5 years. Due to work-related demands as a farmer, he often slept 3 to 4 hours per night and sustained strenuous physical activity. His wife reported snoring and cessation of breathing during the night. Moreover, she noted sleep talking and dream-enactment behaviors; however, neither she nor the patient were injured as a result of these episodes. The patient remembered unpleasant dreams with fearful animals (such as snakes) since teenage-hood. He did not report cataplexy, sleep paralysis, or hypnagogic hallucinations. His daytime sleepiness was assessed with the Epworth Sleepiness Scale, which scored 16 out of 24, indicative of severe excessive daytime sleepiness. BMI was normal; the general and neurologic examinations were in the normal range.

The patient underwent a laboratory full night video-polysomnography, which demonstrated the absence of sleep-disordered breathing (Respiratory Disturbance Index less than 5 events per hour, no significant oxygen desaturations) and documented difficulty falling asleep, total sleep time of 370 minutes, poor sleep efficiency (80%), reduced presence of slow wave sleep, and continuous snoring without related arousals. Neither REM without atonia nor parasomnias were detected. During the consecutive 3 days of observation in the sleep center, sleeping almost 6 hours per night, the patient did not show clinically detectable diurnal hypersomnolence, as confirmed by the normal values obtained at the Multiple Sleep Latency Test performed after the video polysomnography.

According to the clinical and sleep studies results, the patient received a diagnosis of “insufficient sleep syndrome associated with snoring”.

Despite the attempts to ameliorate his sleep hygiene, sporadic use of hypnotics, and a temporary remission of his symptoms, after 2 years the patient developed more hypersomnolence, but he did not undergo new clinical controls until 15 years later. In the meantime, he experienced 2 near-miss car crashes with his tractor.

At the second sleep evaluation, at the age of 69, the patient reported longer nighttime sleep in the last 2 years as compared to the period of the first sleep studies: around 5 hours per night in spring/summer and 7 or 8 hours per night in autumn/winter but he experienced sleep attacks under any circumstances. He usually woke up once or twice at night due to urinary necessity and breathing events. He usually took naps of about 15 minutes, 2 or 3 times per week, judging them unrefreshing. His wife reported episodes of possible dream-enactment behaviors. The BMI was still normal. Since the age of 67, the patient has been under antihypertensive treatment with a diuretic in the morning.

The patient underwent a first full night video polysomnography, which demonstrated a total sleep time of 390 minutes and poor sleep efficiency (76.5%). REM sleep latency was normal, REM sleep percentage was reduced (15%), and REM sleep without atonia was absent. RDI was 15.6 events per hour associated with oxygen desaturation index of 15.1 events per hour and T90 was less than 30%. Neither REM nor non-REM parasomnias events were detected. No pulmonary disease was diagnosed.

Consistent with the finding of moderate obstructive sleep apnea syndrome, the patient underwent a second video polysomnography the following night for continuous positive airway pressure titration, which resulted in good control of the apneic events, persistent reduced sleep efficiency (75.2%), and a total sleep time of 6 hours. REM sleep latency was still normal, and its presence was slightly reduced.

The patient underwent a Multiple Sleep Latency Test after the night of continuous positive airway pressure titration: the test documented pathological values indicative of excessive daytime sleepiness (mean sleep latency of 5.4 minutes) without anticipations of REM sleep. The Multiple Sleep Latency Test was followed by a 24-hour polygraphic Holter EEG comprehending a night with continuous positive airway pressure utilization, which demonstrated a total 24-hour sleep of 7 hours, without daytime naps, no anticipations of REM sleep, and persistent poor sleep efficiency (76.4%).

The final diagnosis was moderate obstructive sleep apnea syndrome and maintaining insomnia with recurrent periods of sleep deprivation due to work-related demands. The patient did not accept the use of hypnotics but only the use of vegetal integrators at bedtime.

After initial difficulties in using continuous positive airway pressure, the patient used the device almost 5 hours per night, 90% of the nights for 3 months with a good control of the diurnal hypersomnolence. Neither car accidents nor near-miss car crashes were reported. The wife did not report abnormal behaviors during sleep.

The patient is under regular annual ambulatory controls with periodic actigraphic monitoring of his sleep-wake profile as well as cognitive assessment to investigate any changes.

Biological basis

Sleep impairments during aging are connected to neurophysiological and neurochemical changes in the brainstem ascending arousal system, thalamus, hypothalamus, and other cortical brain regions. Altered light inputs to melanopsin retinal cells have a pivotal role in the age-related dysregulation of circadian sleep-wake rhythm. Several mechanisms are interdependent whereas others are not, and this explains the high interindividual variability in sleep alterations among older adults of the same age. Primary sleep disorders and other factors such as medication use, nocturia, chronic pain, hormonal changes, psychiatric conditions, and medical comorbidities can contribute to sleep disturbances among the elderly.

Etiology and pathogenesis

Inflammation plays a pivotal role in the cellular senescence and proinflammatory cellular phenotypes are associated with several age-related diseases and dementia risk. A study on 29 individuals aged 61 to 84 years demonstrated that a partial night sleep deprivation induced a change in leukocytes towards the expression of genes connected to senescence, DNA response to damage, and p16, a protein that can inhibit cell cycle progression. Other leukocyte studies confirmed the hypothesis that sleep disturbances and insomnia are linked to inflammation and cellular senescence, all processes involved in aging and cognitive decline. Sleep disturbances can stimulate stress responses such as noradrenergic activity that can act on the immune system and upregulate inflammatory systemic responses. In the sleep-wake transition, the central noradrenergic tone increases while glymphatic clearance decreases with less glymphatic clearance of neurotoxic proteins. Moreover, the proinflammatory microglial activation can increase the risk of nonhealthy aging and Alzheimer disease (51).

On the other hand, several sleep disturbances (insomnia, restless legs syndrome, sleep-disordered breathing, excessive daytime sleepiness) and sleep structure changes occur in inflammatory and immunologic diseases with possible mutual enhancement (18).

Obstructive sleep apnea is highly connected to a proinflammatory state that can contribute to cognitive decline. In patients with obstructive sleep apnea, several circulating biomarkers connected to Alzheimer disease and vascular dementia (beta amyloid and tau proteins, inflammatory cytokines, antioxidants and oxidized products, homocysteine, and clusterin) are altered. Several obstructive sleep apnea and dementia biomarkers alterations can be reversed by continuous positive airway pressure treatment. New evidence suggests that the treatment of obstructive sleep apnea, starting in midlife, is important to prevent cognitive decline (22; 07; 03; 60). Results from Memories, one prospective clinical trial on the use of continuous positive airway pressure in older adults with mild cognitive impairment and obstructive sleep apnea, demonstrated that correct treatment adherence significantly improved cognitive function at 1-year follow-up (86).

Moreover, neurodegenerative processes such as beta amyloid deposition and neurofibrillary tangles are associated with sleep disturbances in a bidirectional manner (46; 68). Since the earliest or preclinical phases of Alzheimer disease and other forms of dementia, subjective and objective measures of poor sleep correlate with beta amyloid burden as well as cerebrospinal fluid levels of beta amyloid and phosphorylated tau (96; 61; 67; 97).

The misalignment between the desired timing of wakefulness and sleep and the ability to fall asleep and maintain sleep is the core of circadian sleep-wake rhythm disorders.

This mismatch can derive from biological or behavioral factors. Circadian sleep-wake rhythm disorders determine altered rest-activity patterns, resulting in more frequent naps during daytime and a minor consolidation of sleep at night, increased irritability, and depressive symptoms. Their prevalence is estimated in up to 10% of adult patients. The phase (timing) of the circadian rhythms of melatonin, temperature, and cortisol have been demonstrated to move earlier (advance) in older persons and the amplitude of these rhythms is reduced. Older adults, including patients with Alzheimer disease and other dementias, may share reduced neuronal activity in the biological clock centers associated with reduced light reaching the back of the eye modified by physiological age-related ocular changes. Amyloid depositions have been found in the retina of patients with Alzheimer disease, particularly in melanopsin cells, in very early stages of the disease, supporting the hypothesis of an early circadian dysfunction in Alzheimer disease (58; 30).

Epidemiology

Sleep as a risk factor for dementia. In studying the incidence and prevalence of dementia (Alzheimer disease in particular), there are several methodological problems linked to the complex etiology, the uncertain onset, and the complex definition of the preclinical phases. Moreover, a particular attention is necessary regarding sex and gender differences and the timing effect of risk factors with age as a driver (87; 72).

A study on the relationship between the age of onset of insomnia (before or after 65 years) and sex on cognition and depressive symptoms demonstrated that the onset of insomnia later in life, insomnia symptoms, excessive daytime sleepiness, and depression were risk factors for cognitive decline in females (52). In men, the risk was represented only by excessive daytime sleepiness and depression. An Italian multicenter study on sleep and circadian dysfunction as markers of mild cognitive impairment and Alzheimer disease revealed some sex differences (44). A confusion-matrices algorithm demonstrated that actigraphic sleep and circadian data had good predictive power (89.87%) in forecasting the disease status (healthy volunteers, mild cognitive impairment, or mild to moderate Alzheimer disease). Sleep regularity was lower in patients with Alzheimer disease compared to controls as well as in males with Alzheimer disease compared to male controls, males with mild cognitive impairment, and females with Alzheimer disease. Mesor was significantly lower in males in the overall population. After adjusting for age, a reduced circadian amplitude was detected in men in the overall population and in subjects with Alzheimer disease but not in mild cognitive impairment. Differences in actigraphic data along aging and dementia trajectories in men and women are intriguing and need to be further elucidated and investigated.

Several longitudinal studies have shown that different sleep disturbances (insomnia, sleep inadequacy, poor sleep, change in sleep duration/quality, or daytime sleepiness) are associated with an increased risk for dementia and Alzheimer disease (81; 47; 09; 92; 19). These data demonstrate that both midlife and late-life sleep characteristics are important risk factors for dementia, emphasizing the need to investigate sleep during different stages of the life course. Insomnia in midlife and long sleep duration or insomnia later in life have demonstrated a higher risk for dementia later in life (93), supporting the “timing hypothesis” of risk factors.

In older adults, both short sleep duration (less than 6 hours per night) and long sleep duration (more than 8 hours per night) are associated with an increased risk for dementia. In some studies, only long sleep duration in midlife (8 hours or more) (104) or late life (9 hours or more) (10) was associated with a higher risk for dementia and Alzheimer disease. These different results are not clearly elucidated and may be due to different follow-up periods and confounders adjusted for. Other limitations may be related to short follow-up periods, small sample sizes, and methodology used for dementia diagnosis. Moreover, some studies were conducted only on male cohorts whereas others only on female or mixed cohorts. Anyway, considering the extensive current epidemiological data, a meta-analysis demonstrated that persons reporting sleep disturbances have a higher risk of incident all-cause dementia, Alzheimer disease, and vascular dementia. Moreover, a subgroup analysis showed that insomnia increased Alzheimer disease but not vascular or all-cause dementia risk. Sleep-disordered breathing was demonstrated to be associated with an increased risk of all cause dementia, Alzheimer disease, and vascular dementia (92); the risk is for neuropathology and clinical syndrome (03; 60).

Prevention

Inadequate sleep is not only a risk factor for neurodegenerative diseases but can represent an opportunity for new treatments and preventative strategies starting in middle age. Dementia-related neuropathology is associated with particular forms of sleep disruption that may be different from or more severe than sleep changes in normal aging. Sleep can be a noninvasive and possible early indicator that can distinguish normal from abnormal aging with possible preventive approaches (68). For example, obstructive sleep apnea treatment can delay the clinical presentation of cognitive impairment and reverse the alterations of biomarkers in the preclinical phases of the disease, contributing to the prevention of dementia (80; 62; 86).

There is an important need for clinicians to detect early signs of sleep disturbance and to recommend evidence-based interventions to mitigate the potential risks.

Differential diagnosis

Confusing conditions

Among older adults with sleep complaints, it is very important to investigate sleep habits, sleep debt, as well as social and environmental aspects, even in the presence of primary sleep disorders. Circadian sleep-wake rhythm disorders are often underestimated, particularly among older adults and those with cognitive decline, because they can be confused with insomnia or excessive daytime sleepiness.

Associated or underlying disorders

Nocturia is common among older adults. Clinicians should consider sleep dysfunction as a contributing factor in patients resistant to therapies targeting the lower urinary tract (103).

Diagnostic workup

In older adults, a detailed clinical history concerning sleep habits, lifestyles, sleep-wake rhythms, and daytime napping is highly recommended. The clinical detection of excessive daytime sleepiness is challenging, and clinicians should dedicate particular attention to this complaint. Salivary melatonin concentrations and body core temperature measurements are important markers of the circadian sleep-wake rhythm, but more data are needed to use them in clinical practice.

Clinicians should systematically screen for obstructive sleep apnea in older adults and patients with mild cognitive impairment and dementia (86). In older women the assessment of primary sleep disturbances and sleep-disordered breathing in particular needs special attention for the possibility of unusual presentations (08).

For the assessment of several primary sleep disorders, instrumental support may be necessary according to specific guidelines, referring the patient to sleep specialists.

Numerous chronic conditions and sleep disturbances are connected in a bidirectional mode, so they have to be investigated and managed together with integrated approaches.

Management

The management of social jet lag, sleep debt, and sleep disturbances since young and middle age may be important in preventing chronic conditions and cognitive decline in older persons. Interventions may include improvements in behavioral routines and sleep hygiene, physical exercise, stress management, and regulation of the exposure levels to natural light (49).

In older adults, primary sleep disorders should be managed according to evidence-based recommendations but with particular attention to some specific age-related aspects. Recommendations for the management of sleep disturbances in older adults can be used, at least in part, even for persons with cognitive decline. These recommendations should be periodically updated: at present there are few double-blind, randomized controlled trials concerning pharmacological and nonpharmacological treatments (12; 45; 109). For instance, cognitive behavioral therapy for insomnia is recommended as the first-line treatment of chronic insomnia (75) but few trials have specifically involved menopausal women and older adults.

Light therapy deserves a special mention, especially for older adults with cognitive decline and Alzheimer disease. Several studies demonstrated that timed exposure to short-wavelength light can ameliorate nighttime sleep efficiency, daytime wakefulness, and evening agitation. Large randomized controlled trials with more targeted light intensities and compliance-enhancing devices are needed (30).

Among older adults, continuous positive airway pressure treatment of obstructive sleep apnea is recommended. It can reduce sleepiness, fatigue, and depressive symptoms, contributing to a better quality of life. In patients with dementia, continuous positive airway pressure improves sleep and agitation, can contribute to reducing cardio and cerebrovascular comorbidities, and possibly can reduce the progression of cognitive decline. In older persons with dementia, compliance to continuous positive airway pressure often requires a valid caregiver, but it is acceptable and does not significantly hinder the therapy (20; 21; 83; 74).