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Insomnia and obstructive sleep apnea as potential triggers of dementia: is personalized prediction and prevention of the pathological cascade applicable?

Authors:

Abstract

Introduction: Sleep disorders ultimately result in sleep deficiency and poor-quality adversely impacts the immune system, glucose metabolism, body weight control, cardiovascular and cerebrovascular function, cognitive function, psychological stability, work productivity, quality of life, and social safety. Sleep disorders are very common among the elderly and are often comorbid with other diseases such as dementia, and further accelerating the underlying neurodegenerative processes. Initial studies have not clearly revealed the relationship between sleep disorders and dementia. Nonetheless, recent findings have suggested that insomnia and obstructive sleep apnea (OSA) are closely associated with dementia and perhaps they could be good predictors of occurrence of dementia and optimal treatments for sleep deficiencies may prevent or delay the onset dementia. Methods: Here, we conducted a systematic review based on the criteria of predictive, preventive, and personalized medicine on the association of dementia in elderlies with sleep disorder, namely insomnia and OSA. We included 7432 studies and analyzed a total of 14 publications after applying appropriate exclusion criteria. Results: We found that OSA patients had a large tendency to develop and/or experience accelerations of both Alzheimer's disease (AD) and also vascular dementia, whereas insomnia patients only develop and/or experience accelerations of AD. This may be reflected in the fact that AD and vascular dementia have similar and at the same time also different mechanisms of action. Several studies have also revealed that treating sleep disorders in elderly patients prevented or delayed the onset of dementia, mitigating the progression of symptoms in patients who already manifested dementic symptoms and even reversing neurodegeneration in particular brain areas. Discussion: Currently, the general medical consensus has poorly addressed the role of sleep disorders in exacerbating the risk of dementia. Critically, studies such as the present one emphasizes that the treatment of sleep disorders could be one the preventive measures to evade or to improve dementia symptoms. Additionally, elderly individuals often manifest different sleep deficiency symptoms than younger ones. Given this, an improved age-specific categorization and evaluation methods for sleep deficiency need to be implemented in diagnosing dementia in order to enable personalized assessments and treatments. Collectively, these findings may also assist to improve efforts in predictively detecting and eventually treating dementia.
1 23
EPMA Journal
ISSN 1878-5077
EPMA Journal
DOI 10.1007/s13167-020-00219-w
Insomnia and obstructive sleep apnea
as potential triggers of dementia: is
personalized prediction and prevention of
the pathological cascade applicable?
Takuro Kitamura, Soichiro Miyazaki,
Harun Bin Sulaiman, Ryota Akaike,
Yuki Ito & Hideaki Suzuki
1 23
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MINIREVIEW
Insomnia and obstructive sleep apnea as potential triggers
of dementia: is personalized prediction and prevention
of the pathological cascade applicable?
Takuro Kitamura
1
&Soichiro Miyazaki
2
&Harun Bin Sulaiman
1
&Ryota Akaike
1
&Yuki Ito
1
&Hideaki Suzuki
1
Received: 9 February 2020 / Accepted: 15 July 2020
#European Association for Predictive, Preventive and Personalised Medicine (EPMA) 2020
Abstract
Introduction Sleep disorders ultimately result in sleep deficiency and poor-quality adversely impacts the immune system,
glucose metabolism, body weight control, cardiovascular and cerebrovascular function, cognitive function, psychological sta-
bility, work productivity, quality of life, and social safety. Sleep disorders are very common among the elderly and are often
comorbid with other diseases such as dementia, and further accelerating the underlying neurodegenerative processes. Initial
studies have not clearly revealed the relationship between sleep disorders and dementia. Nonetheless, recent findings have
suggested that insomnia and obstructive sleep apnea (OSA) are closely associated with dementia and perhaps they could be
good predictors of occurrence of dementia and optimal treatments for sleep deficienciesmay prevent ordelay the onset dementia.
Methods Here, we conducted a systematic review based on the criteria of predictive, preventive, and personalized medicine on
the association of dementia in elderlies with sleep disorder, namely insomnia and OSA. We included 7432 studies and analyzed a
total of 14 publications after applying appropriate exclusion criteria.
Results We found that OSA patients had a large tendency to develop and/or experience accelerations of both Alzheimersdisease
(AD) and also vascular dementia, whereas insomnia patients only develop and/or experience accelerations of AD. This may be
reflected in the fact that AD and vascular dementia have similar and at the same time also different mechanisms of action. Several
studies have also revealed that treating sleep disorders in elderly patients prevented or delayed the onset of dementia, mitigating
the progression of symptoms in patients who already manifested dementic symptoms and even reversing neurodegeneration in
particular brain areas.
Discussion Currently, the general medical consensus has poorly addressed the role of sleep disorders in exacerbating the risk of
dementia. Critically, studies such as the present one emphasizes that the treatment of sleep disorders could be one the preventive
measures to evade or to improve dementia symptoms. Additionally, elderly individuals often manifest different sleep deficiency
symptoms than younger ones. Given this, an improved age-specific categorization and evaluation methods for sleep deficiency
need to be implemented in diagnosing dementia in order to enable personalized assessments and treatments. Collectively, these
findings may also assist to improve efforts in predictively detecting and eventually treating dementia.
Keywords Insomnia .Obstructive sleep apnea .Dementia .Alzheimers disease .CPAP .Cognitive function .
Predictive preventive personalized medicine
Introduction
Alterations in sleep structure, such as a shorter sleep duration,
increased arousal events, and sleep fragmentation, decreased
deep non-rapid eye movement (NREM) sleep which is also
known as slow wave sleep (SWS);decreased rapid eye move-
ment (REM) sleep are very often observed in elderly subjects.
These age-related sleep changes may contribute to neurolog-
ical changes in some subcortical brain regions, such as the
brainstem ascending arousal system, thalamus, and
*Takuro Kitamura
kitamura@med.uoeh-u.ac.jp
1
Department of Otorhinolaryngology-Head and Neck Surgery,
University of Occupational and Environmental Health, 1-1,
Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
2
Research Institute of Life and Sciences, Chubu University,
Kasugai, Japan
EPMA Journal
https://doi.org/10.1007/s13167-020-00219-w
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hypothalamus, together with select cortical regions [1]. Any
type of sleep disturbance is found to be highly associated with
objective and subjective cognitive decline even in healthy
elderlies [2]. Cognitive decline left untreated leads to mild
cognitive impairment (MCI) and eventually to dementia and
often manifest in elderlies. Degeneration of sleep-specific
brain areas, such as the suprachiasmatic nucleus, in
Alzheimers disease (AD) and other dementias often occurs
with the presence of sleep disturbances [3] and altered sleep-
wake patterns. Interactions between dementia and sleep disor-
ders may also be bidirectional. Studies in both animal models
and in humans have suggested that sleep deficiencies lead to
amyloid-β(Aβ) deposits in the brain [4,5], a key component
of AD pathology. Whereas, the accumulation of Aβin brain
regions critical for sleep process is a typical pathological char-
acteristic of AD [6]. Impairment of sleep structure is promi-
nently exaggerated in MCI and AD patients compared to nor-
mal cognitively functioning elderlies [79].
Dementia in elderlies are often associated with the dynamic
changes of a number of biomarkers which begins in midlife
and goes through a transition over a period of 10 to 25 years
prior to the manifestations of severe symptoms [10]. Sleep
deficiencies may also contribute to neurodegeneration-
induced neuroinflammation [11]. Furthermore, sleep disrup-
tions can increase synaptic and neuronal activity, which in
turn dysregulates brain Aβproduction in both mice and
humans [12].
Among the main mechanism contributing to the Aβde-
posits accumulation is the lack of NREM SWS due to high
occurrence of sleep fragmentations and shorter total sleep du-
ration (J. Kent Werner et al. 2017). Glymphatic clearance of
Aβbasically occurs during NREM SWS [4].
The aim of the present review was to survey literatures to
determine the predictive role of the most common sleep dis-
turbances, which are insomnia and obstructive sleep apnea
(OSA), in the incidence of dementia.
In the future, preventive measurements should be used to
evade or to improve dementia symptoms and additionally,
elderly individuals who are undergoing different sleep disor-
ders need personalized age-specific categorization and evalu-
ation methods for its personalized assessments and treatments
for dementia symptoms [1316].
Terminology: sleep disorder
Depending on the field of studies, scientific societies, journals,
and other aspects, there are a quite number of terminologies
describing the abnormality of an optimal sleep such as sleep
disorder, sleep disturbance, sleep deprivation, sleep deficien-
cy, sleep fragmentation, dysgraphia, and many others.
Ultimately however, the main concern of any type of sleep
abnormalities addresses its impact on the normal or healthy
structure of the sleep itself. Hence, in this review, we use the
term sleep disorderto indicate the state of pathological de-
fective sleep process.
Sleep disorder may include the condition where subjects
spending shorter duration of sleep compared to the optimum
duration needed. One of the widely known conditions of this
is insomnia. Insomnia symptom profiles can be categorized as
sleep onset insomnia, sleep maintenance insomnia, combina-
tion of both, and neither criterion [17]. Another is a low sleep
efficiency where subjects have relatively sufficient duration of
sleep, nevertheless having fragmented sleep or imbalance of
sleep stages, which ultimately leading to a sleep deficiency
state. Some subjects may have subjective excessive daytime
sleepiness or other apparent symptoms related to sleep disor-
der, whereas others may not. This low efficiency sleep may be
caused by several know sleep disorders such as OSA, restless
leg syndrome, etc.
Method
Data sources
This systematic review was conducted in accordance with
Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) [18]. We executed a systematic
search from several main databases including MEDLINE/
PubMed, Scopus, and Cochrane library to sort out studies
and researches reporting on the association between sleep de-
ficiency, namely insomnia and OSA with dementia. The
search keywords used are as follows.
sleep OR insomnia OR snoring OR sleep disordered
breathing OR sleep apnea OR obstructive sleep apnea OR
sleep disturbances OR sleep disorder OR sleep problems OR
sleep quality OR sleepiness OR somnolenceAND dementia
OR Alzheimers disease OR vascular dementia.
The search keywords were combined into pairs, e.g., sleep
apnea AND dementia. The search was limited to English lan-
guage and publications up until April, 2020. In addition, we
also included articles from the reference lists and other related
articles that matched our inclusion criteria. Almost all articles
are acquired in the form of PDF or Word files.
Type of studies
The inclusion criteria applied for sorting were (1) high associa-
tions between sleep disorder and dementia, (2) dementia diag-
nosed accordingly to international standard, (3) availability of
medical records, (4) longitudinal study, and (5) sleep disorder
detected by self-reported symptoms, subjective evaluation ques-
tionnaires, objective measurements of sleep variables, or sleep
related clinical findings. The exclusion criteria were (1) case
reports, conference abstracts, reviews, or commentaries; (2)
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cross-sectional study; and (3) main concern of the study is not
dementia, AD, or vascular dementia. In order to avoid overlaps
of study subjects, if any same target population were applied in
plural publications, we adopted only the publication that used the
highest number of subjects. The recruiting process of relevant
publication is shown in detail in a flowchart in Fig. 1.
Depending on each study and its diagnostic formats, the di-
agnostic criteria of dementia was based on the National Institute
of Neurological Disorders and Stroke, Alzheimers Disease and
Related Disorder Association, International Statistical
Classification of Diseases and Related Health Problems, or
Diagnostic and Statistical Manual of Mental Disorders (5th edi-
tion). The diagnostic criteria of insomnia and OSA were based
on International Classification of Sleep Disorder (3rd edition).
Type of study subjects
We included participants who were diagnosed with dementia,
AD, cognitive impairment, or vascular dementia and also have
a history of or ongoing OSA or insomnia. Limitations on
clinical factors and other demographic variables such as age,
sex, race, BMI, and others were not taken into account.
Results
Out of 7432 studies included and analyzed for this review, 14
studies were included in this systematic review. Three studies
[1921] found that OSA and dementia are associated but there
were no studies to report the opposite (Table 1). There were
six [2227] studies reporting that insomnia and dementia are
associated and four [2831] reporting the opposite. One study
[32] assessed the association of insomnia and OSA to demen-
tia and found a high hazard ratio for both sleep disorder.
Discussion
OSA and dementia
Recent meta-analysis studies revealed that middle-aged adults
with OSA also have multiple deterioration in cognitive do-
mains. The main cognitive declines are seen in selective at-
tention (concentration), sustained attention (vigilance), epi-
sodic and/or working memory, and executive and/or motor
function. Despite all these, the domains that govern psycho-
motor, linguistic, and visuospatial functionality were mini-
mally impacted [33]. Middle-aged adults (40 year old and
above) with OSA were 26% more likely to develop significant
cognitive decline or if remained untreated progress into de-
mentia in 3 to 15 years [34]. Untreated OSA can worsen the
vulnerability of the brain due to the gradual deterioration of its
structure and functionality [35]. Consequently, in the occur-
rence of neurodegenerative events, the chronic apneic brain
tends to be vulnerable to its clinical manifestations of demen-
tia [36].
Studies aer removed duplicates
n = 7,065
Studies screened for tles / abstracts (n = 54 )
Full-text arcles assessed for eligibility
n =14
longitudinal studies included
n =14
Excluded for non-English
n = 662
Full-text arcles excluded, with reasons n =40
Relaonship not studied n =10
Demena not assessed n =5
No availability of medical records n =4
Not longitudinal study n =17
Sleep disorder was not detected n =4
Studies excluded (n = 6,349)
Aer screened for tles / abstracts
Studies idenfied through database searching (n = 7,432)
(MEDLINE/PubMed=5477, Scopus=1937, Cochrane library=18)
Duplicates removed
(n =367)
Studies aer removed non-English
n = 6,403
Idenficaon
ScreeningEligibility
Included
Fig. 1 Flowchart PRISMA of Systematic Review in OSA, insomnia, and dementia
EPMA Journal
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Table 1 Longitudinal studies of insomnia and OSA as a risk of dementia
Author Year Total
sample
Age at baseline
(year)
Follow-up
duration
(year)
Sleep variables Type of sleep
disturbance
Diagnosis of dementia Main findings
Morgan et al.
[29]
1994 84 > 65 4 Self-reported insomnia Insomnia DSM-IIIR Insomnia was not associated with the risk of dementia
Forley et al.
[30]
2001 2356 76.6 ± 3.9 3 Self-reported insomnia Insomnia DSM-IIIR Insomnia was not associated with the risk of dementia
Elwood et al.
[31]
2011 1986 55 69 10 Self-reported insomnia Insomnia NINCDS criteria Insomnia was not associated with incident
vascular dementia
Osorio et al.
[22]
2011 346 75.9 ± 6.5 7.7 Self-reported insomnia Insomnia DSM-IV and
NINCDS-ADRDA
Insomnia was significantly associated with AD (OR =2.39)
Yaffe et al.
[19]
2011 298 82.3 ± 3.2 4.7 Objective OSA OSA DSM-IV OSA was associated with risk of dementia (adjusted
RR = 1.86)
Chen et al.
[23]
2012 34,158 > 50 3 ICD-9 diagnostic insomnia Insomnia ICD-9 Insomnia was significantly associated with risk of
dementia (HR = 2.34)
Jaussent et al.
[31]
2012 4894 > 65 8 Self-reported insomnia Insomnia DSM-IV Insomnia complaints was notassociated with risk of dementia
Chang et al.
[20]
2013 8484 > 40 5 ICD-9 diagnostic sleep apnea OSA ICD-9 OSA was associated with risk of dementia (Adjusted
RR = 1.70)
Benedict et al.
[24]
2015 1574 49.6 ± 0.6 40 Self-reported insomnia Insomnia DSM-IV and
NINCDS-ADRDA
Sleep disturbances were associated with risk of
dementia (HR = 1.33)
Tsapanou
et al. [25]
2015 1041 79.3 ± 6.4 3 Self-reported insomnia Insomnia DSM-IIIR and
NINCDS-ADRDA
Insomnia was not associated with risk of dementia
Yaffe et al.
[32]
2015 179,738 > 55 14.3 ICD-9 diagnostic insomnia and
sleep apnea
Insomnia and
OSA
ICD-9 Insomnia was associated with risk of dementia
(HR =1.29). OSA was associated with risk of dementia
(adjusted RR = 1.23)
Hung et al.
[26]
2018 51,734 > 20 7 ICD-9 diagnostic insomnia Insomnia ICD-9 Primary insomnia had a higher risk of developing
dementia than those without primary insomnia
(adjusted RR = 2.14)
Sindi et al.
[27]
2018 1446 >50 310 Self-reported insomnia Insomnia ICD-9 Midlife insomnia and late-life terminal insomnia or
long sleep duration were associated with a higher late-life
dementia risk
Bubu et al.
[21]
2019 1639 > 55 2.52 ± 0.51 Self-reported OSA OSA DSM-IV and
NINCDS-ADRDA
OSA is related to longitudinal increases in amyloid and tau
burden in cognitively normal and mild cognitive
impairment (MCI) OSA patients
EDS excessive daytime sleepiness; DSM-IIIR diagnostic and statistical manual of mental disorders, 3rd edition revised; DSM-IV diagnostic and statistical manual of mental disorders, 4th edition; NINCDS-
ADRDA National Institute of Neurological and Communicative Diseases and Stroke and Alzheimers Disease and Related Disorders Association; ICD-9International statistical classification of disease, 9th
revision; OSA obstructive sleep apnea; AD Alzheimers disease; OR odds ratio; RR risk ratio; HR hazard ratio
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Since OSA and dementia often merge, several large-scale
studies suggest that OSA influences the progression of de-
mentia and may even be used as predictor for dementia at an
earlier age. A longitudinal study by Sharafkhaneh et al. [37]of
more than 4 million patients (average participant age:
57.6 years) examined by the Veterans Health Administration
revealed that the risk for dementia was 1.18 times higher
among those with an OSA diagnosis than among healthy con-
trol subjects. Furthermore, a 4.7-year follow-up study of 298
nondemented subjects aged 65 years and above by Yaffe et al.
[19] revealed a 1.8 times higher risk for MCI or dementia in
patients with OSA. Similarly, a 5-year prospective study by
Chang et al. [20] including 1414 patients with OSA revealed a
1.7 times higher risk of dementia in patients with OSA than in
healthy control subjects and 3.2 times higher risk in female
subjects aged above 70 years (Table 1).
In addition to dementia, OSA may also influence the pro-
gression of cognitive disorders. A study of sleep quality in
patients with dementia conducted by Aoki et al. [38]reported
that patients with dementia and moderate or severe OSA had
significantly worsen dementia severity than those with a lesser
OSA severity. This finding was even more pronounced in
patients younger than 80 years. These results suggest that
OSA not only influences the progression of dementia but also
adversely affects the progression of cognitive dysfunction. In
all the studies stated above however, the severity of OSA and
its impact on the severity of dementia was not studied in detail.
Mechanisms underlying OSAs role in the progression
of dementia
OSA may contribute to dementia via several mechanisms
(Fig. 2). Deposition of Aβ, the fundamental protein
implicatedin dementia, may be one of the most critical factors
mediating these mechanisms.
A further potential mechanism involves blood vessel dys-
function. The intermittent hypoxemia caused by OSA results
in cerebral blood vessel and nerve system degeneration via
multiple pathways. Two of these are microvasculature degen-
eration [39] (caused by vascular endothelial dysfunction,
chemical reactions, and blood pressure elevations) and degen-
eration of the white matter of the cerebrum and the hippocam-
pus due to chronic cerebral hypoperfusion. Buratti et al. [40]
evaluated vascular degeneration using carotid artery ultraso-
nography in AD patients. These authors revealed deteriorated
cerebrovascular reactivity against the intima complex thick-
ness and altered carbon dioxide loads in patients with OSA-
related complications. They also reported aggravated vascular
degeneration with OSA in a small subset of AD patients.
Dysregulated oxygen saturation has been implicated as a
potential bridging mechanism between neurodegeneration
and vascular degeneration or dysfunction. Using
polysomnography (PSG) features to detect postmortem brain
pathology, Gelber et al. [41] found that in 167 Japanese
American subjects who were an average of 84 years old, sleep
duration with a peripheral capillary oxygen saturation (SpO
2
)
< 95% was associated with an increased number of
microinfarcts (adjusted odds ratio = 3.88). Specifically, the
authors found that individuals with more than 71.6% of their
sleep achieving less than 95% SpO
2
experienced 3.88 times
greater levels of microinfarcts than those who experienced
less than 13.1% of their sleep with less than 95% SpO
2
.
Several additional studies have also evaluated cerebral mor-
phological changes using MRI and found hippocampal, fron-
tal lobe, and gray matter degeneration in OSA patients
[4244]. Collectively, these results demonstrate that brain
health is negatively affected by OSA.
Accumulation of amyloid-β
Neuroinflammation
Disrupting neurogenesis
Obstructive sleep
apnea
Alzheimer’s disease Vascular dementia
Insomnia
Intermittent hypoxia
Oxidative stress
Fig. 2 Pathological pathway of
dementia caused by OSA and
insomnia
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In addition to intermittent hypoxia, less deep sleep due to
sleep fragmentation and increased numbers of arousal events
also occur in OSA, posing a potentially significant risk to
cognitive function. In one study [45], neurophysiological test-
ing and fMRI were combined to determine that OSA led to
declines in working memory speed, which were further attrib-
uted to decreased activity in the dorsolateral prefrontal cortex.
Pointing to the supremacy of sleep disturbances and fragmen-
tation, this relationship was found to be more highly associat-
ed with sleep fragmentation than nocturnal hypoxia.
In addition to the findings discussed above, excessive day-
time sleepiness (EDS), a typical symptom of OSA, is also
considered to be a risk factor for vascular dementia. This
was clarified by Elwood et al. [30] in a 10-year-long prospec-
tive cohort study of 1225 male subjects wherein those with
EDS were found to have4.44 times higher risk for developing
vascular dementia.
As stated above, even though the mechanisms underlying
dementia are mainly attributed to vascular lesions or neural
degeneration mediated by intermittent hypoxia, these may al-
so be intricately related to a number of other factors, such as
alterations in sleep structure and EDS.
Effects of treatments for OSA as the preventive
measures of dementia
The most typical and widely applied treatments for OSA are
nasal continuous positive airway pressure (CPAP) devices,
oral appliances, and upper airway surgeries. Among these,
CPAP may be the most common and most effective treatment
for moderate to severe OSA in elderly patients. The greatest
advantage of this particular treatment method is that an ade-
quate treatment efficacy is attainable even in severe OSA
cases by simply applying positive air pressure to prevent air-
way collapse. It is widely acknowledged that this does not
only improve subjective and objective sleepiness but also
neurocognitive functionality as well.
Many studies have shown treatment for OSA potentially
has positive effects as for preventive treatments for cognitive
decline, impairment, or dementia. Canessa et al. [43]investi-
gated the correlations between cerebral MRI findings and cog-
nitive functioning in 17 severe OSA patients and 15 normal,
age-matched control subjects (average age: 44). The authors
found that cognitive function declined in patients with severe
OSA. In these patients, declines were also correlated with
reductions in hippocampal, cerebral, left posterior parietal cor-
tex, and right superior frontal gyrus gray matter density.
Nevertheless, after 3 months of CPAP treatment, significant
improvements in these patientscognitive functioning and
gray matter density were observed.
A recent large-scale study [46] conducted by the
Alzheimers Disease Neuroimaging Initiative in America
found that OSA may influence the progression of MCI and
AD. The authors also reported a high likelihood that CPAP
contributes to mitigating the progression of cognitive dysfunc-
tion. In this study, 2470 subjects between the ages of 55 and
90 years were divided into three groups: MCI, AD, and nor-
mal. The onset age of MCI and AD, the presence of OSA
symptoms, and CPAP treatment history for each group were
reported. Patients who were diagnosed with MCI or AD and
who exhibited OSA symptoms were found to first manifest
MCI symptoms at an average age of 77 years, whereas pa-
tients without OSA symptoms manifested MCI symptoms at
90, on average. Meanwhile, the symptomatic manifestation of
AD in patients with OSA symptoms started at an average age
of 83 years, while in those without OSA symptoms, it mani-
fested at 88. Additionally, patients who underwent CPAP
treatment began to exhibit MCI and AD symptoms 10 years
and 5 years, respectively, after those who did not undergo
CPAP treatment.
In a randomized study of 33 OSA patients (average age:
71), a 3-month CPAP treatment improved short-term memo-
ry, working memory, selective attention, executive function-
ality, and fight middle frontal gyrus functional connectivity
[47]. In another preliminary study, CPAP treatment on
nondemented cohort of elderly subjects were found to delay
MCI onset age by approximately 10 years (72 vs. 82 years
old). Furthermore, the MCI onset age of OSA group was near
to non-CPAP group, indicating that treatment of OSA can
mitigate neurodegenerative processes [46]. In a case study
on OSA patients with subjective cognitive impairment
showed that CPAP treatment for 1 year normalized the
CSF Aβ42 and t-tau/Aβ42 ratios and also the cognitive
complains [48]. This may suggest that OSA has a poten-
tial as a reversible risk factor for dementia. On the con-
trary, however, in another randomized trial, 1 year of
CPAP treatment showed no significant effect on cognitive
function in subjects aged 65 and older, despite having
significant improvement in sleepiness [49]. The absence
of improvement in cognitive functionality in this study
could be caused by a ceiling effect, where the subjects
showed normal cognitive functions at baseline. This,
which in turn can be viewed as a predictive and person-
alization for CPAP administration, where elderly subjects
with manifestation of cognitive functionality impairment
at baseline need treatment for OSA more than those with
normal performance at baseline.
Given that symptoms such as daytime sleepiness and ail-
ments like cardiovascular disease in elderly OSA patients are
both pathologically and clinically distinct from those in a
younger population, some may great the prospect of treating
elderly OSA patients with some skepticism. Nevertheless, this
review indicates that the treatments for OSA that are also
found to be most promising from the perspective of cognitive
health and cerebral pathology, such as CPAP, should be
employed more broadly.
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CPAP, however, is not well tolerated by all patients. Here,
a personalized treatment for OSA must be considered. Some
CPAP treatment may end in failure with no significant im-
provements despite the high compliance and in some cases,
patients may refuse to continue using. In such cases, other
alternative treatments should be considered.
The first alternative is oral appliances only if the CPAP treat-
ment remains unsuccessful even after maximum effort. Criteria
for patients who meet the best compliance for oral appliances
were extensively reviewed [50]. Some oral appliances function
to advance the mandible forward during sleep to maintain upper
airway dilation, others hold tongue forward avoiding it to col-
lapse onto the upper airway. This review overall concluded that
in mild to severe OSA, only 52% of cases were able to control
airway maintenance. Patients with severe OSA and very high
BMI showed more resistance to the treatment since more fat
and soft tissue in the nasal pharyngeal were not affected by these
types of oral appliances. As for the overall evaluation, oral appli-
ances showed less effectiveness than CPAP, which was greater
than 80% in maintaining airway. One other aspect to consider in
oral appliances are the side effects upon adherence such as man-
dibular joint pain, tooth pain, dry mouth, and tongue pain. All
these ultimately lead to an adverse effect of sleep disorder itself
where the patients experience more sleep fragmentations due to
the frequent arousals caused by the side effects stated above.
Another alternative treatment is surgical interventions to widen
the upper airway for patients with very low compliance or im-
provements after CPAP and oral appliances. One of the most
performed surgical procedures for OSA is
uvulopalatopharyngoplasty (UPPP), which was overall less suc-
cessful as OSA treatment compared to CPAP and oral appliances.
Only 33% of patients experienced the same improvement of
CPAP and oral appliance treatment [51]. This surgical method is
more likely to achieve successful improvements in OSA patients
who did not show significant improvement with CPAP and oral
appliances and with mild OSA and normal BMI. Obese patients
with higher BMI have excessive adipose tissue in the lateral
parapharyngeal area, the tongue, and the neck. This surgical meth-
od has its limitation where it cannot directly address the fat stored
at these sites.
To prevent dementia, it is clear that early stage interven-
tions are critical, regardless of OSA onset age. Future random-
ized clinical trials with larger sample size and longer duration
of therapy is necessary and may think about targeting with a
high-risk group (e.g., people with MCI).
Insomnia and dementia
Insomnia is a type of sleep disorder characterized by difficulty
falling and/or staying asleep. Specifically, individuals with
insomnia experience one or more of the following symptoms:
difficulty falling asleep, frequent waking during the night with
trouble going back to sleep, waking early in the morning, and
fatigue uponawakening.Insomnia isone of the mostcommon
sleep complaints among elderly adults, with a prevalence of
nearly 50% in those aged 65 years and older [52]. In recent
years, a number of studies have suggested a high rate of in-
somnia and dementia comorbidity. Given this, insomnia has
attracted attention as possible dementia risk factor or initial
symptom. For instance, in one 3-year follow-up longitudinal
study of 1041 non-dementia individuals aged over 65 years,
those who developed dementia (75 subjects) reported
experiencing daytime vigilance difficulties, while those unaf-
fected by dementia (966 subjects) did not [25]. Additionally,
subjects who developed dementia also reported inadequate
nocturnal sleep. These results suggest a correlation between
daytime somnolence and the development of dementia.
Daytime somnolence and nocturnal sleep deprivation should
further be considered to be risk factors for dementia and could
be used as predictor for it.
Epidemiological studies have been mixed, with some show-
ing links between insomnia and dementia and others showing
none. In an Italian epidemiological survey of 750 elderly indi-
viduals aged over 65 years (664 normal subjects and 86 dementia
subjects), 85% were found to have insomnia [53]. Critically, this
study found no significant differences in sleep onset latency,
nocturnal awakening, OSA, or restless leg syndrome rates be-
tween normal patients and those with dementia. It did report,
however, that dementia patients slept significantly more during
the day than did controls. Conversely, another study of 3857
nondemented individuals aged over 65 years reported a hazard
ratio of 1.58 for dementia-specific mortality among those who
averagedmorethan9hofdailysleeprelativetothosewho
averaged less than 9 h [54].
In particular, the association between insomnia and dementia
risk has also been examined. In one such systematic review and
meta-analysis, de Almondes et al. [55] identified five population-
based prospective cohort studies [2224,29,31] that examined
this association more closely. This analysis revealed that insomnia
was associated with a significant risk for all-cause dementia (risk
ratio = 1.53). However, another systematic review and meta-
analysis by Shi et al. [56], which examined four additional pro-
spective studies [25,28,30,32], found that insomnia was not a risk
factor for all-cause dementia. Interestingly, Shi et al. also reported
that insomnia had differential effects of sleep on dementia sub-
types. Specifically, insomnia increased the risk for developing AD
but had no effect on vascular dementia. Discrepancies in meta-
analysis results may be attributable to differences in the designs of
the studies and variability in participantssubtypes of dementia
(Table 1).
Mechanisms underlying insomnia role in the
progression of dementia
Insomnia may contribute to dementia via several mechanisms
(Fig. 2). Aβ, the fundamental protein implicated in dementia,
EPMA Journal
Author's personal copy
may be one of the most critical factors mediating these mech-
anisms. Studies in both animal models and in humans have
suggested that sleep deficiencies lead to Aβdeposits in the
brain [4,5], a key component of AD pathology. Sleep defi-
ciencies may also contribute to neurodegeneration-induced
neuroinflammation [11]. Furthermore, sleep disruptions can
increase synaptic and neuronal activity, which in turn
dysregulates brain Aβproduction in both mice and humans
[12]. As insomnia patients tend to have insufficient duration of
NREM sleep, glymphatic clearance of Aβduring NREM may
be slowed down.
Effects of treatments for insomnia as the preventive
measures of dementia
As described above, sleep disturbances are commonly found
in patients with cognitive impairments and vice-versa. Studies
done to determine the effectiveness of interventions for in-
somnia may secondarily facilitate the prevention of dementia
in high-risk populations. Thus, it is critical to evaluate whether
these insomnia interventions also mitigate cognitive decline.
One common intervention used for the treatment of insom-
nia is melatonin supplementation, which may also have indi-
rect effects on cognition. Serum melatonin decreases with
aging and more prominently low in insomnia patients.
However, the direct effects of melatonin onto sleep structure
of insomnia patients and its potential onto cognitive decline
remain controversial. For example, in one 4-week trial, mela-
tonin administration of 1 mg nightly improved verbal memory
and slight improvements in other cognitive function tests [57].
In another 6-month trial, administration of 2 mg of prolonged
release melatonin showed positive effects on cognitive func-
tioning and sleep maintenance in AD patients, particularly in
those with insomnia comorbidity [58]. Melatonin has been
demonstrated to prevent Aβ
2535
-induced circadian alter-
ations [59], Aβ-induced oxidative stress [60], and lipid per-
oxidation [61].
On the other hand, for instance, Xu et al. [62] summarized
seven randomized controlled trials of melatoninseffectson
cognition and concluded that melatonin did in fact increase
sleep duration and sleep efficiency in patients with dementia
but did not offer any significant benefits for cognitive
functioning.
Melatonin replacement for insomnia patients must be care-
fully administered due to its duration of effect in the body.
Oral administration melatonin is available mainly in two
types. One is immediate release and the another is prolonged
release [60,6365]. Depending on the manifestation of in-
somnia symptoms on individuals, physicians need to assess
the appropriate type for each patient. Some insomnia patients
have high SOL but low WASO; on the other hand, others may
have the opposite of this, and some have both these com-
plexes. Another variable of melatonin administration to take
into account is the dose dependency [66]. Each insomnia pa-
tient requires different dose for an optimum efficacy of sleep
depending on age, BMI, sex, comorbidities, and working
hours [6769]. Additionally, sleep hygiene education is also
very important to achieve a constant sleep circadian rhythm.
The melatonin administration timing needs to be precisely
followed since the duration required for it to initiate sleep
may differ among patients. Furthermore, light exposure at
night time would also interfere with the melatonin function.
All these details for treatment must be carefully planned in
order for an effective and reliable long-term personalized
medication. A mismatch of melatonin type, dose, timing,
and interactions with other drugs may cause adverse effects
such as somnolence, EDS, fatigue, and other conditions.
Apart from melatonin, some additional preventive or ther-
apeutic measures have also been investigated in the context of
cognitive dysfunction or dementia and insomnia. For instance,
exercise has been shown to improve sleep quality among the
elderly and potentially improve cognitive functioning in sub-
jects with or without cognitive impairments [70]. Between
sleep treatments and cognitive outcomes, bright light therapy
may also be a promising, low-risk treatment for sleep prob-
lems. In a recent meta-analysis by Van Maanen et al. [71], the
authors concluded that while most effect sizes were only small
or medium, light therapy was effective for sleep problems in
general, and particularly for circadian outcomes and insomnia
symptoms.
Another alternative for non-pharmacological and non-
invasive method is cognitive behavioral therapy for chronic
insomnia (CBT-i). This therapy successfully improves long-
term sleep quality and cognitive decline in insomnia patients
[72]. CBT-I intervention may be a strong candidate of treat-
ment as insomnia it is markedly present in aging, MCI, and
AD where it in turn increases the risk factor for developing
AD.
Conclusions and expert recommendations
It will be of grave importance for physicians, researchers,
caregivers, and patients themselves to correctly comprehend
about each individuals tendencies of sleep disorder in order to
take correct preventive measures. The present review briefly
described a pathogenic risk for dementia that is associated
with sleep disorders. Particularly, insomnia may increase the
risk for AD onset, and OSA is a risk factor for the develop-
ment of both AD and vascular dementia (Fig. 2). The predic-
tive role of the most common sleep disorders which are OSA
and insomnia could be also used as a predictive standard for
dementia. A general clinical consensus indicates that dementia
prevention in high-risk patients involves both early stage di-
agnosis and other necessary patient-personalized
EPMA Journal
Author's personal copy
interventions. Careful evaluation of sleep structure in these
patients should also be highly considered.
Middle-aged subjects having insomnia or OSA may develop
or accelerate benign pre-existing dementia in a course of approx-
imately 15 years. Pre-clinical changes in the brain need to be
assessed and personalized treatment for each patient is crucial
in order to prevent or delay the onset of severe dementia.
Furthermore, to block the aggregation of cerebral Aβand
facilitate its excretion, discrete and early stage interventions
for insomnia and also OSA need to be implemented.
Superficial improvements in patient education around sleep
hygiene and lifestyle may not be sufficient. It is likely that
broader benefits can be achieved with these essential and po-
tentially significant clinical treatments of insomnia and OSA
in dementia patients and those at greatest risk.
In any event where patients make a visit to medical centers
about sleep problems or cognitive decline, the physicians han-
dling sleep problems should not only perform sleep tests but
also work on a collaborative test with neurology departments
to perform cognitive tests as well. The same approach should
be made by neurologists regarding sleep tests.
In the case of middle-aged patients with mild symptoms, pre-
vention measures for sleep disorder or cognitive functions must
be prioritized and a long-term treatment should be advised. These
patients need to be given necessary education on sleep and cog-
nitive as well. Some patients may also be given lifestyle guidance
in order to avoid further progression of the symptoms.
In the case of patients with symptoms which have
progressed, a personalized treatment should be implemented
carefully. As the cognitive functionality declines, it will be
even challenging for the patients themselves to maintain a
healthy lifestyle. Here, not only treatments but alsoeducations
for patients caretakers need to be thoroughly given.
Lastly, the authors would also like to strongly emphasize
the crucial necessity of large scaled studies on the various
types of sleep disorders for the ascertainments of the demo-
graphics of the general population in order to achieve better
prediction and prevention measures on any kind of sleep dis-
orders itself long before developing any kind of neurodegen-
erative disorder such as dementia.
Limitation
In this systematic review, we focused mainly on the associa-
tion of dementia to insomnia and OSA; however, we did not
include other sleep disorders such as sleep wake rhythm
changes and hypersomnia, or other pathologies such as chron-
ic fatigue syndrome that may cause or exacerbate dementia.
Funding information This work was supported by a Grant-in-Aid for
ScientificResearch(C)(no.16K11251)fromtheJapaneseSociety
for the Promotion of Science.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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... Hence, treating sleep disorders would be beneficial in preventing and delaying the onset of dementia, and in improving the condition. [56][57][58][59][60][61][62][63][64][65][66][67] 8 ...
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Dementia is a neurological condition characterized by numerous types of central nervous system diseases, which gradually deteriorates an individual’s reasoning, rational thinking, and judgment abilities. As a serious public health concern that currently affects more than 50 million older adults, dementia is one of the most significant causes of incapacity, disability, and dependency among older adults. As new cases are expected to increase exponentially in the next three decades, dementia, which is not a normal feature of healthy aging despite the fact that it generally affects older adults disproportionately, requires enormous management and care efforts due to its associated socioeconomic, psychological, and physical burdens that involve the patient, their caregivers, guardians, family members, and society at large. Presently, there is no cure for dementia; however, this condition could be prevented. This narrative review aimed to provide a broad overview of studies detailing the alternative lifestyle modification-centered preventive measures against dementia. A comprehensive search of key databases to find articles related to this topic revealed that participating in regular physical activities, healthy eating and dieting, avoiding all forms of smoking, avoiding air pollutants, halting or reducing alcohol consumption, exercising the mind and being socially dynamic, getting enough rest and establishing good sleeping habits, infection prevention, stress prevention, avoidance of injuries, preventing the effects of social isolation and lockdowns, continuing education, and depression prevention are protective measures against the development of dementia.
... Multiple studies have shown that OSA is linked with increased Alzheimer's disease (AD) markers (Daulatzai, 2015;Lutsey et al., 2018;Bubu et al., 2019;Kitamura et al., 2020), including the beta amyloid levels (Bu et al., 2015;Sharma et al., 2018). These levels increase with time in non-treated OSA patients, suggesting that untreated individuals with OSA or OSA subjects with noncomplaint continuous positive airway (CPAP) treatment are at heightened risk for developing AD (Li et al., 2015;Cholerton et al., 2016;Liguori et al., 2017;Mullins et al., 2020). ...
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... Moreover, OSAHS is also an independent risk factor for the morbidity and death of cardiovascular, hypertension and cerebrovascular diseases (such as atherosclerosis, arrhythmia and ischemic heart disease), seriously affecting people's health and quality of life 11 . Some patients with severe cognitive impairment caused by OSAHS may develop Alzheimer's disease 12 . It is believed that the increased risk of cardiovascular and cerebrovascular diseases, respiratory failure and cognitive impairment is mediated by several mediating mechanisms, such as sympathetic activation and oxidative stress 13 . ...
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... Contextually, individualised sleep quality monitoring is essential to analyse individual sleep patterns, to predict sleep disorders and associated pathologies followed by targeted prevention and treatments tailored to the personalised patient profile [9,[11][12][13][14]. This approach is conform with principles of predictive, preventive and personalised medicine (PPPM/3PM) [15]. ...
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... Contextually, individualised sleep quality monitoring is essential to analyse individual sleep patterns, to predict sleep disorders and associated pathologies followed by targeted prevention and treatments tailored to the personalised patient pro le [9,[11][12][13][14]. This approach is conform with principles of predictive, preventive and personalised medicine (PPPM / 3PM) [15]. ...
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Sleep quality and duration as well as activity-rest-cycles at individual level are crucial for maintaining physical and mental health. Although several approaches do exist to monitor these parameters, optimal approaches are still under consideration and technological development. Wrist actigraphy is a non-invasive electro-physical method validated in the field of chronobiology to record movements and to allow for monitoring human activity-rest-cycles. Based on the continuous recording of motor activity and light exposure, actigraphy provides valuable information about the quality and quantity of the sleep-wake rhythm and about the amount of motor activity at day and night that is highly relevant for disease prediction, targeted prevention and personalisation of medical services. Being generally used in the field of sleep medicine, actigraphy demonstrates a great potential to be successfully implemented in primary, secondary and tertiary care, psychiatry, oncology, and intensive care, military and sports medicines as well as epidemiological monitoring of behavioural habits as well as well-being medical support, amongst others. Prediction of disease development and individual outcomes Activity-rest-cycles have been demonstrated to be an important predictor for many diseases including but not restricted to the development of metabolic, psychiatric and malignant pathologies. Moreover, activity-rest-cycles directly impact individual outcomes in corresponding patient cohorts. Targeted prevention Data acquired by actigraphy are instrumental for the evidence-based targeted prevention by analysing individualised patient profiles including light exposure, sleep duration and quality, activity-rest-cycles, intensity and structure of motion pattern. Personalised Therapy Wrist actigraphic approach is increasingly used in clinical care. Personalised measurements of sedation/agitation rhythms are useful for ICU-patients, for evaluation of motor fatigue in oncologic patients, for an individual enhancement of performance in military and sport medicine. In the framework of personalised therapy intervention, patients can be encouraged to optimise their behavioural habits improving recovery and activity patterns. This opens excellent perspectives for the sleep-inducing medication and stimulants replacement as well as for increasing the role of participatory medicine by visualisation and encouraging favourable behavioural patterns of the individual.
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Increasing evidence links cognitive-decline and Alzheimer's disease (AD) to various sleep disorders, including obstructive sleep apnea (OSA). With increasing age, there are substantial differences in OSA's prevalence, associated comorbidities and phenotypic presentation. An important question for sleep and AD researchers is whether OSA's heterogeneity results in varying cognitive-outcomes in older-adults compared to middle-aged adults. In this review, we systematically integrated research examining OSA and cognition, mild cognitive-impairment (MCI) and AD/AD biomarkers; including the effects of continuous positive airway pressure (CPAP) treatment, particularly focusing on characterizing the heterogeneity of OSA and its cognitive-outcomes. Broadly, in middle-aged adults, OSA is often associated with mild impairment in attention, memory and executive function. In older-adults, OSA is not associated with any particular pattern of cognitive-impairment at cross-section; however, OSA is associated with the development of MCI or AD with symptomatic patients who have a higher likelihood of associated disturbed sleep/cognitive-impairment driving these findings. CPAP treatment may be effective in improving cognition in OSA patients with AD. Recent trends demonstrate links between OSA and AD-biomarkers of neurodegeneration across all age-groups. These distinct patterns provide the foundation for envisioning better characterization of OSA and the need for more sensitive/novel sleep-dependent cognitive assessments to assess OSA-related cognitive-impairment.
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