The Importance of Diagnosing and the Clinical Potential of Treating Obstructive Sleep Apnea to Delay Mild Cognitive Impairment and Alzheimer's ...
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Journal of Alzheimer’s Disease Reports 5 (2021) 515–533 515
DOI 10.3233/ADR-210004
IOS Press
Review
The Importance of Diagnosing and the
Clinical Potential of Treating Obstructive
Sleep Apnea to Delay Mild Cognitive
Impairment and Alzheimer’s Disease: A
Special Focus on Cognitive Performance
Mariana Fernandesa , Fabio Placidia,b , Nicola Biagio Mercurib,c and Claudio Liguoria,b,∗
a Sleep
Medicine Centre, Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy
b NeurologyUnit, University Hospital of Rome Tor Vergata, Rome, Italy
c IRCCS Fondazione Santa Lucia, Rome, Italy
Accepted 19 May 2021
Pre-press 5 June 2021
Abstract. Obstructive sleep apnea (OSA) is a highly frequent sleep disorder in the middle-aged and older population, and it
has been associated with an increased risk of developing cognitive decline and dementia, including mild cognitive impairment
(MCI) and Alzheimer’s disease (AD). In more recent years, a growing number of studies have focused on: 1) the presence
of OSA in patients with MCI or AD, 2) the link between OSA and markers of AD pathology, and 3) the role of OSA in
accelerating cognitive deterioration in patients with MCI or AD. Moreover, some studies have also assessed the effects of
continuous positive airway pressure (CPAP) treatment on the cognitive trajectory in MCI and AD patients with comorbid
OSA. This narrative review summarizes the findings of studies that analyzed OSA as a risk factor for developing MCI and/or
AD in the middle-aged and older populations with a special focus on cognition. In addition, it describes the results regarding
the effects of CPAP treatment in hampering the progressive cognitive decline in AD and delaying the conversion to AD in
MCI patients. Considering the importance of identifying and treating OSA in patients with MCI or AD in order to prevent or
reduce the progression of cognitive decline, further larger and adequately powered studies are needed both to support these
findings and to set programs for the early recognition of OSA in patients with cognitive impairment.
Keywords: Alzheimer’s disease, cognitive impairment, continuous positive airway pressure, neuropsychological function,
sleep-disordered breathing
INTRODUCTION Alzheimer’s disease (AD) [1–3]. OSA is a highly
frequent sleep disorder, and it is characterized by
A growing number of studies have documented an repeated episodes of upper airways obstruction dur-
association between obstructive sleep apnea (OSA) ing sleep, causing intermittent hypoxia (IH), sleep
and the increased risk of cognitive decline and fragmentation (SF), and excessive daytime sleepi-
ness (EDS). Polysomnography (PSG) is considered
∗ Correspondence to: Claudio Liguori, MD, PhD, Department the gold standard tool for OSA diagnosis [4], which
of Systems Medicine, University of Rome “Tor Vergata”, is made through the assessment of physiological
Via Montpellier 1, 00133 Rome, Italy. Tel.: +390620902107;
signals during sleep, namely from oronasal airflow,
Fax:+390620902116; E-mail: dott.claudioliguori@yahoo.it.
ISSN 2542-4823 © 2021 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms
of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).516 M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD respiratory effort, and pulse oximetry. Further, the In more recent years, growing attention was given apnea-hypopnea index (AHI) reflects OSA severity to the associations between OSA, markers of AD degree and is defined as the number of respiratory pathology, and the development of cognitive impair- events (apneas and hypopneas) per hour of sleep. ment and the progression to dementia. Regarding OSA syndrome is diagnosed when patients present the prevalence of OSA in AD, a quantitative meta- an AHI ≥ 5 events/h on PSG coupled with reporting analytical study [37] documented that patients with symptoms of impaired daytime function, or AHI ≥ 15 AD have a five times higher likelihood of present- events/h [5]. The global recommendation is to start ing OSA when compared to cognitively unimpaired OSA treatment as soon as the diagnosis is made [5]. individuals of similar age. This meta-analysis, based It has been recently evidenced that OSA can impair on five cross-sectional studies, detected that around brain and body health since it has been associated 50% of patients with AD experienced OSA at some with diabetes, hypertension, metabolic syndrome, time after their initial diagnosis. However, few stud- and depression [6–15]. Therefore, OSA represents ies were evaluated and all were conducted in the late a growing healthcare problem affecting middle-aged 1980s [37]. and older adults with several clinical consequences Most of the narrative reviews published in the last [6, 9–13, 15–20]. Consistently, OSA is associated year focused on the possible explanatory mechanisms with different medical disorders, and it has also been linking OSA to dementia, as well as explored demen- recognized as a risk factor for AD; moreover, OSA is a tia biomarkers in OSA [3, 38–40]. common comorbidity in patients with mild cognitive Indeed, OSA has been currently considered a risk impairment (MCI) as well as AD dementia (ADD), factor for AD [41], since it can induce or aggravate with rates of prevalence up to 40% [21, 22]. neurodegenerative mechanisms such as amyloid- The overall prevalence of OSA in the general pop- (A) pathology [16, 18], oxidative stress, synaptic ulation is still to be re-defined worldwide, since it dysfunction, and neuroinflammation [40]. has been estimated to be between 2 and 4%, with There were also other systematic and meta-reviews an increased rate in middle-aged and older adults focused on how OSA affects specific neurocogni- [23–25]. Consistently, a recent population-based tive domains in adults; nevertheless, the findings study reported a prevalence of moderate-to-severe reported were inconsistent [42, 43] and sometimes sleep-disordered breathing of 23.4% in women and non-conclusive [44, 45]. The only meta-review focus- 49.7% in men [6]. ing on OSA and cognition in older adults reported OSA treatment can depend on disease severity, a weak association between OSA and cognitive symptoms and contributing causes. The treatment of impairment, concluding that only specific popula- choice for OSA is continuous positive airway pres- tions of OSA patients may be at risk of cognitive sure (CPAP), although surgical approaches, oral dev- decline [46]. Recently, a systematic review [47], ices, pharmacological therapies, and oropharyngeal including 68 studies, documented that OSA is fre- muscles stimulators have emerged as an efficacious quently associated with mild impairment in attention, treatment against OSA [26–31]. Past literature, fol- memory, and executive functions in middle-aged lowing the evidence that OSA can impair cognition, adults, whereas it is not associated with any par- thus causing attention deficit and memory impair- ticular pattern of cognitive impairment in older ment, demonstrated that CPAP can restore cognitive adults. This systematic review [47] also examined performances both in young and in cognitively unim- some randomized controlled trials (RCTs) evaluat- paired patients [32]. On the other hand, in spite of ing the effects of CPAP treatment and suggesting the some recent evidence stating that OSA can increase relation between improvement of sleep parameters the risk of developing cognitive impairment and (slow-wave sleep – SWS and EDS) and cogni- dementia (AD or vascular dementia), several stud- tive performances in AD patients with OSA. Other ies have focused on proving that CPAP treatment can studies highlighted the effects of CPAP treatment improve neuropsychological performances also in in modifying AD biomarkers among older adults patients with cognitive impairment [33–36]. Hence, with comorbid OSA and AD. In spite of taking any intervention that enhances cognition in patients all this recently published literature into account with dementia is likely to have a wider impact, since [32, 38], the present review will not be focusing improving daily function may lead to a patients’ on AD biomarkers changes in patients with OSA, greater independence, lower caregiver burden, and but it will focus instead exclusively on AD-related lesser nursing assistance and social support. cognitive function in patients with OSA and the
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD 517
effects of CPAP on these cognitive domains in mid- Considering the very limited literature investigat-
dle-aged and older adults. ing the prevalence of OSA in patients with MCI,
Hence, the current narrative review of the litera- Dlugaj et al. [7], using a community-based sam-
ture aims at combining two important aspects linking ple, found a similar OSA prevalence in patients with
OSA to MCI or AD: on the one hand, it analyses the and without MCI (27% and 26%, respectively), and
impact of OSA on the possible development of MCI no association between MCI or MCI sub-types and
and/or AD in the middle-aged and adult populations OSA-severity. Similarly, Kim and colleagues [48]
from a cognitive point of view; on the other hand, it found no association between MCI and the AHI in a
describes the effects of CPAP treatment in hampering clinic-based sample of patients. However, the authors
the progressive cognitive decline in AD and delaying documented that higher AHI was associated with
the clinical conversion to AD in MCI patients. The lower language test performance among individuals
methodology of the study is described in Box 1. with MCI and it was not present in controls, suggest-
ing that OSA can mainly impair language in patients
OSA AS A RISK FOR DEVELOPING MCI with MCI.
AND AD Although more studies have been conducted in
patients with AD, they date back to the 1980s and
Several studies have examined the relation between reported controversial results; two studies [49, 50]
OSA and MCI in the last decade. However, studies demonstrated a significant association between AD
focusing on the association between OSA and AD and OSA diagnoses, whereas three studies did not
diagnosis are few and mainly conducted in commu- find any relations [51–53]. As aforementioned, a
nity samples and nursing homes. Table 1 presents the recent meta-analysis including these five studies
summary findings from 17 studies that considered the [37] concluded that the aggregate odds ratio for
relation between OSA and cognitive functioning in OSA in patients with AD was five times higher
MCI and AD patients, which will be discussed in when compared to cognitively unimpaired individ-
detail in this section. uals of similar age. Moreover, high AHI was related518
Table 1
Studies’ characteristics and main findings: OSA and MCI/AD
Authors, Study Design, Participants OSA Cognitive Adjusted Variables Main Findings
Year Setting and assessment Assessment: Tests
Published Country and Diagnostic
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
Criteria
Patients Controls
N Gender N Age N Age
Chang Longitudinal, 8,464 5,034 M 1,414 40% – 7,050 40% – Clinical Dementia diagnosis Age, sex, CVD OSA was associated
et al., 2013 community based, 3,450 F OSA 40–49 y Non-OSA 40–49 y diagnosis (ICD-9) based on comorbidities, with increased
[56] Taiwan 30.9% – 30.9% – ICD-9 income, dementia risk within
50–59 y 50–59 y criteria urbanization 5 years, and OSA
15.5% – 15.5% – was found to be
60–69 y 60–69 y gender, age, and
13.6% 13.6% time-dependent.
–≥70 y –≥70 y
Dlugaj Cross-sectional, 1,793 919 M M = 63.8 AHI Neuropsy- OSA model OSA not associated
et al., 2014 population-based, 874 F (SD = 7.5) chological test adjusted: Age, sex, with MCI or MCI
[7] Germany battery to assess education.Poor sleep subtypes. Poor sleep
memory and quality model quality was
executive functions adjusted also: BMI, associated with
diabetes, systolic MCI.
blood pressure,
coronary heart
disease, APOE e4,
smoking,
antidepressant use,
benzodiazepine use,
severe depressive
symptoms and pure
alcohol intake.
Foley Cross-sectional, 718 Only men 27.2% with PSG Cognitive Age, education, and OSA was associated
et al., 2003 The ≥ 85y AHI impairment assessed marital status with more
[59] Honolulu-Asia ESS through Cognitive drowsiness, but not
Aging Study of Abilities Screening with poor cognitive
Sleep Apnea, Instrument functioning.
HawaiiHoch Cross-sectional, 139 33 M 34 AD M = 71.5 56 HC M = 69.3 PSG, AHI Dementia diagnosis None A significant
et al., 1986 USA 47 F (SD = 8.1) (SD = 5.4) based on DSM-III association between
[49] criteria the AHI and severity
of dementia in
apnea-positive AD
patients, as well as
in the entire sample
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
of AD patients.
Hoch Cross-sectional, 27 7M 15 OSA M = 74.5 12 M = 70.2 PSG, AHI AD diagnosis was None Overnight mental
et al., 1989 Geriatric units, 20 F (SD = 5.1) Non-OSA (SD = 5.6) made through status deterioration
[52] senior clubs, USA NICNDSS-ADRDA was not associated
and DSM-III with measures of
criteria, OSA.
Global cognition
(MMSE and CDR)
Jorge Longitudinal, 125 72 F 81 OSA M = 74.0 44 M = 76.0 PSG, Neuropsychological Age, sex, body mass No significant
et al. 2020 Cognitive 53 M Non-OSA AHI test battery to assess index, HTA, difference in any
[62] Disorders Unit, memory, language pharmacological cognitive
Spain and praxis. treatment and subdomains at 12
Alzheimer status months and no
differences among
OSA severity groups
in patients with mild
to moderate AD.
Kim Cross-sectional, 60 42 M 30 MCI M = 67.4 30 HC M = 68.0 PSG, MCI diagnosis was Gender A significant
et al., 2011 Clinic, 18 F (SD = 3.8) (SD = 4.1) AHI made using association between
[48] South Korea CERAD-K criteria severe OSA and
Neuropsychological impaired language
battery to assess function in MCI
executive function, patients.
language, memory
and visuospatial
construction
Lee Longitudinal, 4,362 3,332 M 727 OSA 48.8% – 3,635 49.7% – NHIS record of Dementia diagnosis Sex, age, CVD, Patients with OSA
et al., 2019 community, 1,030 F 40–49 y Non-OSA 40–49 y clinical diagnosis based on ICD-10 hypertension, Type were 1.575 times
[57] Republic of Korea 34.9% – 30.4% – criteria 2 Diabetes, more likely to
50–59 y 50–59 y depression, BMI, develop AD than
14.2% – 14.0% – smoking status, those without OSA
60–69 y 60–69 y physical activity,
2.06% – 2.94% – and drinking
≥70 y ≥70 y
(Continued)
519520
Table 1
(Continued)
Authors, Study Design, Participants OSA Cognitive Adjusted Variables Main Findings
Year Setting and assessment Assessment: Tests
Published Country and Diagnostic
Criteria
Patients Controls
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
N Gender N Age N Age
Lutsey Longitudinal, 966 469 M M = 61.3 Home PSQ, AHI Executive function, Age, sex, field OSA category and
et al., 2016 community, USA 497 F (SD = 5.0) memory and centre, education; additional indices of
[60] language were ethanol intake, sleep were not
assessed through smoking status, associated with a
Digit leisure-time change in any
Symbol Substitution physical activity, cognitive test.
Test, APOEe4, BMI,
Delayed Word high-sensitivity
Recall Test C-reactive protein,
Word Fluency Test diabetes mellitus,
hypertension, and
prevalent coronary
heart disease, heart
failure, or stroke.
Lutsey Longitudinal, 1,667 790 M 818 OSA M = 63.6 849 M = 62.0 Home PSQ, AHI Dementia and MCI Age, sex, education, Late-midlife severe
et al., 2018 Community, USA 877 F (SD = 5.4) (SD = 5.5) were assessed field centre, physical OSA was associated
[61] through TICSm and activity, drinking, with all-cause and
neurocognitive exam smoking status, ADD in later life.
leisure time, APOE
e4, BMI
Osorio Prospective, 195 138 M 12 MCI M = 74.6 50 MCI 98 M = 72.1 Self-reported MCI and AD APOE e4 status, A significant
et al., 2015 ADNI cohort, 57 F 35 AD (SD = 5.8) AD (SD = 5.9) diagnosis made by a sex, education, BMI, association between
[2] USA M = 73.1 M = 71.9 clinician depression, OSA and earlier age
(SD = 6.6) (SD = 6.9) cardiovascular at cognitive decline.
disease,
hypertension,
diabetes, and age
Reynolds Cross-sectional, 61 19 M 21 AD M = 70.3 23 HC M = 69.3 PSG, AHI Dementia diagnosis Sex A significant
et al., 1985 USA 42 F (SD = 7.9) (SD = 5.6) based on DSM-III association between
[50] criteria, MMSE, OSA and dementia
CDR and a modified in women.
Hachinski Ischemia
scoreReynolds Cross-sectional, 30 3M 15 M = 73.3 15 M = 72.6 24 Chanel Dementia diagnosis None No association
et al., 1987 USA 27 F (SD = 9.1) (SD = 7.8) polygraphs based on DSM-III between OSA and
[51] criteria, MMSE, dementia.
CDR and a modified
Hachinski Ischemia
score
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
Smallwood Cross-sectional, 55 45 M 15 M: M = 65.5 40 M: M = 60 AHIRespiratory AD diagnosis based Age, sex No relation between
et al., 1983 Media Solicitation 10 F (SD = 2.3) (SD = 1.31) inductive on DSM-III criteria, OSA and dementia.
[53] and AD Centers, F: M = 69.5 F: M = 65.5 plethysmo-graphy Neurological
USA (SD = 4.4) (SD = 2.2) examination
Tsai Retrospective 19,890 13,110 M 3,978 OSA 70.5%: 15,912 70.5%: ICD-9 CM, NHIRD AD diagnosis based Sex, age, OSA was
et al. 2020 cohort study, 6,780 F 40–59 y Non-OSA 40–59 y CPAP, surgeries, on ICD-9 CM urbanization level, independently
[58] Taiwan 29.5%:≥ 29.5%:≥ drugs criteria income, and associated with an
60 y 60 y comorbidities. increased risk of
AD. Treatment for
OSA reduces the
AD risk in OSA
patients.
Yaffe Longitudinal, 298 Women 105 OSA M = 82.6 193 M = 82.1 PSG, AHI > 15 Neuropsychological Age, race, BMI, Higher Hypoxemia
et al., 2011 Community, USA Only (SD = 3.1) Non-OSA (SD = 3.2) test battery to assess education, smoking, had a higher risk of
[54] cognitive diabetes, developing MCI or
impairment: Global, hypertension, dementia over a 5y
Attention, Executive antidepressant use, follow-up. Sleep
Function, Memory, benzodiazepine use, fragmentation and
MMSE non-diazepam duration not
anxiolytics use associated with
cognitive
impairment.
Yaffe Retrospective 179,738 Men Only 4,107AD ≥55y Clinical diagnosis AD and Dementia Age, CVD Those with OSA
et al., 2015 cohort study, 14,380 D diagnosis based on comorbidities, had a 20% and 27%
[55] USA 2,715 VaD ICD-9 criteria obesity, depression, increased risk for
5,82 LBD income, education AD and dementia,
respectively.
AD, Alzheimer’s disease; AHI, Apnea-Hypopnea Index; BMI, body mass index; CDR, Clinical Dementia Rating; CERAD-K, Korean version of Consortium to Establish a Registry for Alzheimer’s
Disease; CPAP, continuous pulmonary airway pressure; CVD, cardiovascular disease; D, dementia; DSM-III, Diagnostic and Statistical Manual of Mental Disorders, third edition; APOE,
apolipoprotein epsilon4; ESS, Epworth Sleepiness Scale; F, female; ICD-9/10, International Classification of Diseases ninth/tenth edition AD criteria; LBD, Lewy body dementia; M, male; MCI,
mild cognitive impairment; MMSE, Mini-Mental State Examination; N, number of participants; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke
and the Alzheimer’s Disease and Related Disorders Association; NHIRD, National Health Insurance Research Database; OSA, obstructive sleep apnea; PSQI, Pittsburg Sleep Quality Index; PSG,
Polysomnography; RCT, randomized clinical trial; TICSm, Telephone interview for cognitive status; VaD, vascular dementia.
521522 M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD to worse cognitive and functional status, suggest- Therefore, the aforementioned data seems to be ing that the severity of OSA increases along AD contrasting, and cannot allow for an interpretation progression. Another recent meta-analysis reported of the causality direction between OSA and AD that individuals with sleep disturbances (insomnia, due to the different methodology and study designs. sleep-disordered breathing, EDS, sleep-wake rhythm Nevertheless, the here presented data highlights the disorders) have a higher risk of developing all-cause hypothesis of a bi-directional relation between OSA dementia, AD, and vascular dementia [41]. In particu- and AD. In particular, the current evidence shows lar, a sub-analysis showed that both snoring and OSA that OSA is frequently comorbid in patients with were associated with an increased risk of all-cause MCI or AD diagnosis [2, 63]. Moreover, OSA may dementia, AD, and vascular dementia. However, represent a risk factor for developing MCI and many of the cited studies used self-reported mea- AD in middle-aged and older adults, boosting and sures to assess OSA and few longitudinal studies were advancing cognitive decline and possibly inducing included. Among them, Yaffe and colleagues [54] in or accelerating AD neurodegenerative processes [54, a sample of older women found that those diagnosed 64]. with OSA by PSG had an increased risk of developing Hence, all these findings support the evidence that MCI or dementia over a 5-year follow-up. In another OSA can increase the risk of MCI or AD, but also study including only older adult male veterans, the suggest a higher incidence of OSA in MCI and authors reported a significant association between AD patients, with a progressive increase of OSA OSA and a higher risk of AD, vascular demen- prevalence along with cognitive deterioration. How- tia and other dementias [55]. Similarly, two large ever, these findings need to be supported by further longitudinal community-based studies proposed the studies, which should overcome some of the cur- same results in the Asian population [56, 57]. In rent limitations of these previous investigations (e.g., particular, Lee et al. [57], from a national repre- cross-sectional studies). Further, there are still few sentative cohort data, found that patients with OSA studies focused on the risk of MCI or AD in patients were almost 1.58 times more likely to develop AD with OSA, mainly because OSA is immediately than those without OSA. In addition, a recent retro- treated when diagnosed, thus making it impossible spective study [58], including 3,978 OSA patients to conduct longitudinal observational studies. and 15,912 non-OSA patients, reported that OSA was independently and significantly associated with a higher incidence of AD, with an average period THE EFFECTS OF CPAP THERAPY ON of AD detection from the time of OSA diagnosis COGNITION estimated as 5.44 years. However, the literature also presents some studies not showing a clear and signif- Several studies reported that CPAP treatment can icant association between OSA and the development improve different cognitive deficits in adult OSA of cognitive impairment and AD [59–61]. In keep- patients, namely executive function, memory, atten- ing with that, Lutsey and colleagues [61] analyzed a tion, and reaction time [32, 65]. Regarding AD pat- group of OSA patients that were followed for over ients, different studies explored the effects of CPAP 15 years and did not find a significant association on cognitive functioning, suggesting the possibility between OSA and risk of dementia. However, when of hampering or retarding the transition from MCI using adjudicated outcomes (i.e., syndromic demen- to AD [2, 66, 67], as well as delaying the cognitive tia and MCI as adjudicated by an expert panel), severe decline in AD [33–35]. Table 2 presents the summary OSA (AHI ≥ 30) was associated with a higher risk findings from the 9 studies that explored the effects of all-cause dementia and AD dementia, but these of CPAP on cognitive functioning in MCI and AD associations were reduced after controlling for car- patients. diovascular risk factors. Moreover, a recent study Few RCTs of CPAP on AD patients were per- documented a non-significant role of comorbid OSA formed; however, there are currently no RCTs of on the longitudinal deterioration of cognitive sub- CPAP in MCI patients co-affected by OSA. Cooke domains or global cognition in a group of 144 AD and colleagues [34], by selecting patients from a 6- patients [62]. These divergent results regarding the week randomized placebo-controlled trial of CPAP in role of OSA on AD raise questionable issues about patients with mild to moderate AD, compared a group the diagnosis and the treatment of OSA in patients of five patients who had sustained CPAP treatment with MCI or AD. after completion of the RCT to a group of five patients
Table 2
Studies’ characteristics and main findings: CPAP on cognitive functioning in MCI and AD patients
Authors, Study Design, Participants OSA assessment Cognitive Adjusted Main Findings
Year Setting and Assessment:Tests Variables
Published Country and Diagnostic
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
Criteria
N Gender Treatment Group Control Group
N Mean age N Mean age
(SD) (SD)
Ancoli- RCT, General 52 39 M 27 78.6 (6.8) 25 Placebo 77.7 (7.7) Rechtschaffen Neuropsychological None After 3-weeks of
Israel clinical research 13 F and Kales test battery to assess CPAP for both AD
et al., 2008 center, USA criteria global cognition, groups, there was a
[33] basic attention and significant
vigilance, improvement in the
psychomotor speed, composite
verbal episodic neuropsychological
memory and score.
executive
functioning
Cooke RCT, 10 7M 5 5 NCCPAP AHI, PSQI, Neuropsychological None Sustained CPAP use
et al., 2009 Follow-up, USA 3F ESS, FOSQ test battery to assess associated with less
[34] global cognition, cognitive decline in
basic attention and patients with AD.
vigilance,
psychomotor speed,
verbal episodic
memory and
executive
functioning
Dunietz Retrospective, 41,466 25,462 M 30,717 10,749 Clinical MCI, AD and Age, sex, race, PAP adherence was
et al., 2021 Medicare 16,004 F NCCPAP Diagnosis and Dementia not stroke, associated with
[70] beneficiaries, issued treatment otherwise specified hypertension, lower odds of
USA were identified with cardiovascular incident diagnoses
ICD-9 codes disease, and of AD.
depression
(Continued)
523524
Table 2
(Continued)
Authors, Study Design, Participants OSA assessment Cognitive Adjusted Main Findings
Year Setting and Assessment:Tests Variables
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
Published Country and Diagnostic
Criteria
N Gender Treatment Group Control Group
N Mean age N Mean age
(SD) (SD)
Ligouri Retrospective, 24 16 M 12 75.2 (4.9) 12 74.4 (6.9) AHI, ESS Global cognition None Decrease in
et al., 2021 Multicenter 8F NCCPAP and dementia cognitive decline
[69] study, Italy assessed through (CDR) between
MMSE, CDR baseline and 1-year
follow-up in MCI
and AD patients.
Osorio Prospective, 195 138 M 12 MCI 74.6 (5.8) 50 MCI 72.1 (5.9) Self-reported MCI and AD APOE e4 status, CPAP treatment
et al. 2015 ADNI cohort, 57 F 35 AD 73.1 (6.6) 98 AD 71.9 (6.9) diagnosis made by a sex, education, delayed age at MCI
[2] USA clinician BMI, onset.
depression,
cardiovascular
disease,
hypertension,
diabetes, and
age
Richards Quasi- 54 34 M 29 67.4 (7.2) 25 73.2 (8.6) PSG; AHI > 10 Memory (Hopkins Age, race, and CPAP adherence in
et al. 2019 experimental; 24 F Verbal Learning marital status MCI and OSA
[67] Sleep and Test-Revised), patients significantly
geriatric clinics Cognitive improved cognition
and community processing speed compared with a
Longitudinal (Digit Symbol), nonadherent control
Global cognition group.
(MMSE), Attention
(Stroop test and
Psychomotor
Vigilance Task)Skiba et al., Retrospective, 96 63 M 42 70.0 (9.4) 24 No CPAP 70.1 (11.3) PSG, AHI Modified CERAD: Age, gender, CPAP use in MCI
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
2020 [71] Urban tertiary 33 F 30 NCCPAP 71.4 (7.7) memory, language. education and patients with OSA
health center, attention executive race was not associated
USA function with a delay in
Global progression to
cognition(CDR). dementia or
cognitive decline.
Troussierè Longitudinal, 23 14 M 14 73.4 9 NCCPAP 77.6 Video PSG Global cognition None CPAP treatment of
et al. 2014 Clinic Centre, 9F AHI ≥ 30, ESS assessed with severe OSA in
[35] France MMSE mild-to-moderate
AD patients was
associated with
slower cognitive
decline over a
three-year follow-up
period.
Wang et al., Quasi- 17 8M 7 68.4 (6.6) 10 NCCPAP 74.6 (9.67) PSG Memory (Hopkins None A year ofCPAP
2020 [66] experimental 9F Verbal Learning adherence improved
clinical, Test-Revised); psychomotor/
Memories 1 Global cognition cognitive processing
data 1-year (Montreal Cognitive speed in older adults
follow-up Assessment) with MCI and mild
Global progression OSA.
(ADCS- CGIC;
CDR)
AD, Alzheimer’s disease; ADCS-CGIC, Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change; AHI, Apnea-Hypopnea Index; BMI, body mass index; APOE, apolipoprotein
epsilon4; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; CDR, Clinical Dementia Rating; CPAP, continuous pulmonary airway pressure; CVD, cardiovascular disease; D,
dementia; DSM-III, Diagnostic and Statistical Manual of Mental Disorders, third edition; ESS, Epworth Sleepiness Scale; F, female; FOSQ, Functional Outcomes Sleep Questionnaire; ICD-9/10,
International Classification of Diseases ninth/tenth edition AD criteria; M, male; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; N, number of participants; NCCPAP,
Non-compliant CPAP; OSA, obstructive sleep apnea; PAP, positive airway pressure; PSQI, Pittsburg Sleep Quality Index; PSG, polysomnography; RCT, randomized clinical trial.
525526 M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD
Fig. 1. Benefits of treating OSA in clinical and neuropathological aspects in patients with MCI and AD.
who had discontinued CPAP. Results showed that AD patients showing severe OSA [34, 35, 68].
sustained CPAP use was associated with less cogni- In particular, a small longitudinal study, including
tive decline, stabilization of depressive symptoms and 23 patients with AD comorbid with severe OSA,
daytime somnolence, and significant improvement reported that the cognitive decline was significantly
in subjective sleep quality. Furthermore, Ancoli- slower in the CPAP group than in the non-CPAP
Israel et al. [33], in a randomized double-blind group through a 3-year follow-up [35].
placebo-controlled trial study in 52 patients with Some retrospective studies have also found an
mild-moderate AD and comorbid OSA, observed no association between CPAP use and cognitive func-
changes in neuropsychological functioning between tioning. For example, Osorio et al. [2], using
treatment groups (3 weeks of active CPAP versus 3 Alzheimer’s disease Neuroimaging Initiative data,
weeks of placebo followed by 3 weeks of CPAP) documented that OSA patients had an earlier onset
but documented in the paired analysis that after three age of MCI or AD and that CPAP use delayed the
weeks of therapeutic CPAP both groups reported an age of MCI onset. However, in this study, OSA
improvement in cognitive functioning. Notably, some diagnosis and CPAP use were self-reported. Another
limitations on these RCTs on AD patients need to be recent, retrospective study [69], found a significant
acknowledged, namely the statistical power and the difference in cognitive and functional performances
use of small samples, which make it harder to draw assessed with clinical dementia rating scale, between
conclusive assumptions on the causality of CPAP on the CPAP non-compliant and the CPAP compliant
cognitive performance. group, with patients CPAP non-compliant reporting
Recently, in a 1-year quasi-experimental trial, a significant longitudinal worsening in cognitive and
Richards et al. [67] found that CPAP adherence functional performances compared to CPAP com-
in MCI and OSA patients, when compared with a pliant patients. In line with these findings, another
nonadherent control group, significantly improved recent retrospective study [70], considering a large
cognition, which suggests that CPAP adherence may sample of patients diagnosed with OSA, documented
slow the trajectory of cognitive decline. Similarly, that PAP adherence was associated with lower odds
Wang and colleagues [66] recently reported a signif- of incident diagnoses of AD. Conversely, Skiba et
icant positive effect of adherent CPAP treatment on al. [71] reported no significant differences between
cognitive functioning in older adults with MCI and CPAP compliant, CPAP non-compliant and no CPAP
OSA (AHI ≥ 10); however, the authors did not exam- use on a sample of 96 MCI patients. However,
ine cognitive outcomes related to the different degree when looking at the timing before conversion, it
of OSA severity. appeared evident that patients CPAP compliant (77.3
Several studies have documented that CPAP treat- months) presented a longer time before conversion
ment may slow cognitive decline in mild to moderate than non-compliant (52.1 months) or non-use (47.3M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD 527
Fig. 2. Possible intermediate detrimental mechanisms in the relation between OSA and cognitive deterioration.
months) CPAP groups. Moreover, the authors found architecture and key sleep parameters [34, 68], which
that patients with amnestic MCI had better CPAP use may, in turn, reduce the risk of metabolic dysfunc-
and shorter progression time to dementia; however, tion, cardiovascular morbidity and mortality, as well
this difference became non-significant after adjust- as decrease the risk of developing depression [74].
ing for age, education, and race. The authors, thus, Figure 1 summarizes the benefits of treating OSA
concluded that the CPAP use in MCI patients with in clinical and neuropathological aspects in patients
OSA was not associated with delay in progression with MCI and AD.
to dementia or cognitive decline. This negative result
contrasts with most of the previous literature and must THE ROLE OF SLEEP PHYSIOLOGICAL
be read carefully since the criteria for OSA diagno- MECHANISMS ON COGNITIVE
sis were not well-defined and different treatments of FUNCTIONING
OSA were considered [72].
The findings of these several studies demonstrated It is well known that sleep plays an important role
that, despite some statistical limitations, there is suf- in the development and maintenance of cognitive
ficient evidence to suggest that CPAP treatment may performance [75]. In particular, sleep quality and con-
be effective in improving cognition in OSA patients tinuity has been demonstrated to ensure brain health.
with MCI and AD. Moreover, treating sleep apnea Healthy sleep habits promote better cognitive perfor-
holds great promise not only to enhance cognition mance given the positive effects of both non-rapid
but also to improve quality of life and delay MCI and eye movement (NREM) and REM sleep stages [75,
AD progression [73, 74]. For instance, several stud- 76]. NREM sleep, especially SWS, reactivates the
ies demonstrated that OSA increases AD biomarker hippocampal-neocortical circuits activated during a
burden and as such, it is plausible to hypothesize waking learning period. REM sleep is responsible for
that CPAP treatment would also result in changes the consolidation of the new learning materials and
of amyloid and tau AD biomarkers. Although there skills [75, 76]. This coupled action of NREM and
are still few studies, one recent report showed that REM sleep during the night permits memory con-
untreated OSA patients present lower cerebrospinal solidation and storage. Further, a link has also been
fluid A42 concentrations, and a higher T-tau/A42 found between brain cholinergic activity, timing, and
ratio when compared to both CPAP-treated individu- density of REM sleep and cognitive functioning [77].
als and controls [16]. Furthermore, CPAP treatment Thus, considering that the AD process impairs the
in MCI and AD patients showed also to be an effective cholinergic network [78, 79], it has been hypoth-
intervention with significant positive effects in sleep esized that deep sleep (SWS and REM) alteration528 M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD can be associated with cognitive deficits in middle- reported that high IL-6 blood levels in OSA patients aged and older adults from the early stages of AD can reflect both the negative effects of the exces- neurodegeneration. sive inflammatory response, triggered by intermittent Sleep deprivation and disruption markedly affect hypoxia and the positive effects of neurogenesis the individuals’ cognitive and emotional abilities against neurodegeneration as an attempt to counteract [80]. In fact, studies consistently show that not the pathological processes induced by OSA [69]. In only sleep architecture and continuity, but also sleep line with this hypothesis, although IH parameters cor- stages and components, such as SWS, REM sleep, related with high IL-6 blood levels in patients with K-complexes, and sleep spindles, have specific and OSA, these high IL-6 blood levels give a reduced crucial roles in neurogenesis [81], synaptic plastic- propensity to develop dementia [108]. ity [82], and next-day vigilance [83], as well as in SF is one of the well-recognized sleep parameters memory formation and consolidation [84, 85]. More- influencing cognition in OSA patients. For insta- over, abnormal sleep duration (both short and long) nce, different reviews have reported an association is associated with lower brain grey matter volume between SF and cognitive impairment in patients in patients with OSA, suggesting the possibility of with OSA, specifically, the severity of SF was asso- future cognitive decline [86]. OSA is characterized by ciated with worse performance in attention and IH and major changes in sleep characteristics, namely vigilance tests [109, 110]. Executive functions were sleep fragmentation (SF), sleep deprivation, SWS also found to be affected by SF in OSA patients. disruption, and a decrease in REM sleep [87–89]. For example, Djnlagic and colleagues [111] found Sleep impairment due to apnea events can acceler- that OSA patients had less overnight improvement ate cognitive decline and trigger brain pathological on the motor sequence learning task when compared events leading to AD neurodegeneration [90]. Fig- to healthy controls. Moreover, the decline in sleep- ure 2 shows the possible intermediate detrimental dependent memory consolidation was associated in mechanisms in the relation between OSA and cog- OSA patients with increasing age, higher arousal nitive deterioration. index and more severe sleep-disordered breathing The association between hypoxemia and some (higher AHI). SF, actigraphy-assessed arousals and cognitive deficits, including attention deficit, slow circadian rhythm disruption have also been associ- processing speed and executive dysfunctions, has ated with increased risk of MCI/dementia in older been widely established in patients with OSA [91– adults [112, 113]. 95]. Notably, IH in OSA promotes the brain accu- Another contributing factor of OSA to cognitive mulation of A42 and tau pathology and can induce impairment is EDS because of its association with neuronal damage [40, 96, 97]. The pathophysio- slowing information speed, alteration in attention, logical effects of IH may also trigger hypertension vigilance, and memory [114]. Accordingly, EDS in [98, 99], impaired glucose metabolism [100, 101], patients with OSA could be related to high AHI, more metabolic consequences [101, 102], neuroinflamma- SF, and low nocturnal oxygenation [114]. However, tion, and oxidative stress [103], which could lead other factors may have a significant role in explain- to cognitive impairment and progress to AD. Con- ing EDS in OSA patients, such as age, sex, obesity, sistently, a recent general population cohort study depression, and other medical illnesses [115]. reported an association between lower mean oxygen In conclusion, OSA may promote neurodegener- saturation during sleep and brain atrophy in corti- ative changes resulting from all three of its main cal and subcortical areas more sensible to hypoxemia consequences: IH, SF, and EDS [40, 43]. These have [104]. Although the detrimental role of IH has been a deleterious impact on cortical and hippocampal net- well established in patients with OSA, controver- works, causing degeneration and necrosis of neurons, sial results have been achieved in different studies which leads to memory impairment, cognitive decline regarding neuroinflammation; in particular, the role and progression to MCI and AD. of interleukin-6 (IL-6) has been recently investigated in patients with OSA. Although higher levels of IL- 6 can significantly improve memory and learning FUTURE PERSPECTIVE processes via its effects on neuronal excitability at hippocampal synapses [105, 106], as an inflamma- Although some double-blinded, placebo-contro- tory cytokine, its effects can also be detrimental and lled clinical trials addressed the effects of CPAP, other induce neurodegeneration [107]. Hence, it has been RCTs are also needed in order to improve the current
M. Fernandes et al. / Treating OSA to Improve Cognition and Prevent MCI and AD 529
methodological issues, which are related to design, with neuropsychiatric symptoms, including sleep dis-
sample size and recruitment. Hence, larger and more orders [119, 120]. This review examined if OSA may
powered samples, as well as different recruitment influence cognitive functioning in patients with MCI
establishments (not only in OSA and CPAP ther- or AD and highlighted the evidence that CPAP treat-
apeutic centers) will benefit empirical research the ment may delay cognitive decline in these patients,
most. Moreover, future RCTs should consider other although further evidence should be obtained. Taking
aspects besides OSA severity (mild, moderate, and all the present literature into account, from a clinical
severe), namely disease duration, hypoxemia and point of view, the need to understand the prevalence
fragmented sleep severity, and presence of other of OSA in patients with AD was clear, as well as
comorbidities. As mentioned before, RCTs of CPAP the incidence of future AD in patients with OSA,
in MCI patients with co-affected OSA should also be in order to assess and manage resources to prevent
conducted. Lastly, future prospective studies among ADD, delaying the transition from MCI to ADD, or
MCI patients should include a clear definition of the slowing cognitive deterioration during the AD pro-
dementia disorder developed during the follow-up cess by treating OSA. Accordingly, the 5th Canadian
(AD versus other dementias), by using the current Consensus Conference highlights the importance of
biomarkers-based criteria for diagnosis, with a reg- screening for dementia in patients with sleep apnea
ular time frame to evaluate CPAP compliance and and recommends that OSA patients be treated with
efficacy concerning cognitive decline. CPAP since it may improve cognition and decrease
Most studies have focused on improving cognitive the risk of dementia [121]. However, some of these
deficits or delaying the cognitive decline by using findings highlighted the importance of starting CPAP
CPAP to treat an OSA condition; however, adherence treatment early but also of improving the follow-up
to CPAP treatment remains the main target for stud- to monitor the compliance to this device. Therefore,
ies since the poor compliance to CPAP represents CPAP may be a promising treatment for slowing
an evident obstacle. Although there are other and cognitive decline in older adults with MCI or AD
emerging treatment options for OSA, namely spe- and comorbid OSA, although other pharmacologi-
cific drugs (solriamfetol and pitolisant for treating cal and non-pharmacological approaches should be
EDS associated with OSA [116, 117] or Atomox- evaluated and tested. Finally, larger and adequately
etine and Oxybutynin for reducing OSA severity powered studies are needed to corroborate the find-
[31]), oral appliances, behavioral/lifestyle modifica- ings presented in this review.
tions, surgery and/or a combination of approaches,
it is still unclear if these OSA treatment options
have similar positive effects on sleep and cognitive CONFLICT OF INTEREST
functioning as CPAP treatment. In particular, by
using an approved drug for cognitive impairment The authors report no conflicts of interests or finan-
and AD, Moraes and colleagues [118] examined cial disclosures.
the effects of donepezil on OSA in a double-blind,
placebo-controlled study including AD patients. The
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