Association of Sleep-Disordered Breathing With Cognitive Function
and Risk of Cognitive Impairment: A Systematic Review Meta-analysis
Leng, Y., McEvoy, C., Allen, I., & Yaffe, K. (2017). Association of Sleep-Disordered Breathing With Cognitive
Function and Risk of Cognitive Impairment: A Systematic Review Meta-analysis.
JAMA neurology
, 1-9.
https://doi.org/10.1001/jamaneurol.2017.2180
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Association of Sleep-Disordered Breathing With Cognitive
Function and Risk of Cognitive Impairment
A Systematic Review Meta-analysis
Yue Leng, PhD; Claire T. McEvoy, PhD; Isabel E. Allen, PhD; Kristine Yaffe, MD
IMPORTANCE
Growing evidence suggests an association between sleep-disordered breathing
(SDB) and cognitive decline in elderly persons. However, results from population-based
studies have been conflicting, possibly owing to different methods to assess SDB or cognitive
domains, making it difficult to draw conclusions on this association.
OBJECTIVE To provide a quantitative synthesis of population-based studies on the
relationship between SDB and risk of cognitive impairment.
DATA SOURCES PubMed, EMBASE, and PsychINFO were systematically searched to identify
peer-reviewed articles published in English before January 2017 that reported on the
association between SDB and cognitive function.
STUDY SELECTION We included cross-sectional and prospective studies with at least 200
participants with a mean participant age of 40 years or older.
DATA EXTRACTION AND SYNTHESIS Data were extracted independently by 2 investigators.
We extracted and pooled adjusted risk ratios from prospective studies and standard mean
differences from cross-sectional studies, using random-effect models. This meta-analysis
followed the PRISMA guidelines and also adhered to the MOOSE guidelines.
MAIN OUTCOMES AND MEASURES Cognitive outcomes were based on standard tests or
diagnosis of cognitive impairment. Sleep-disordered breathing was ascertained by
apnea-hypopnea index or clinical diagnosis.
RESULTS We included 14 studies, 6 of which were prospective, covering a total of 4 288 419
men and women. Pooled analysis of the 6 prospective studies indicated that those with SDB
were 26% (risk ratio, 1.26; 95% CI, 1.05-1.50) more likely to develop cognitive impairment,
with no evidence of publication bias but significant heterogeneity between studies. After
removing 1 study that introduced significant heterogeneity, the pooled risk ratio was 1.35
(95% CI, 1.11-1.65). Pooled analysis of the 7 cross-sectional studies suggested that those with
SDB had slightly worse executive function (standard mean difference, −0.05; 95% CI, −0.09
to 0.00), with no evidence of heterogeneity or publication bias. Sleep-disordered breathing
was not associated with global cognition or memory.
CONCLUSIONS AND RELEVANCE Sleep-disordered breathing is associated with an increased
risk of cognitive impairment and a small worsening in executive function. Further studies are
required to determine the mechanisms linking these common conditions and whether
treatment of SDB might reduce risk of cognitive impairment.
JAMA Neurol. doi:10.1001/jamaneurol.2017.2180
Published online August 28, 2017.
Supplemental content
Author Affiliations: Department of
Psychiatry, University of California,
San Francisco (Leng, McEvoy);
School of Medicine, Dentistry, and
Biomedical Sciences, Queen’s
University, Belfast, United Kingdom
(McEvoy); Department of
Epidemiology and Biostatistics,
University of California, San Francisco
(Allen); Department of Psychiatry,
University of California, San Francisco
(Yaffe); Department of Neurology,
University of California, San Francisco
(Yaffe); Department of Epidemiology,
University of California, San Francisco
(Yaffe); San Francisco VA Medical
Center, San Francisco, California
(Yaffe).
Corresponding Author: Yue Leng,
PhD, Department of Psychiatry,
University of California,
San Francisco, 4150 Clement St,
San Francisco, CA 94121
(yue.leng@ucsf.edu).
Research
JAMA Neurology | Original Investigation
(Reprinted) E1
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S
leep-disordered breathing (SDB) is a very common but
treatable condition in older adults. There has been grow-
ing interest in the relationship between SDB and ad-
verse health consequences, including hypertension, diabe-
tes, and cardiovascular diseases.
1-4
While the association
between SDB and health outcomes remains controversial, es-
pecially in older populations,
5-8
recent evidence has sug-
gested a link between SDB and cognitive decline in elderly
persons.
9-11
Notably, most early studies have examined the as-
sociation between SDB and cognition in clinical populations,
eg, among patients at sleep clinics.
12-14
These studies usually
consist of individuals with relatively severe SDB and were lim-
ited by small sample sizes and failure to account for confound-
ing factors.
Over the past few years, an increasing number of popula-
tion-based studies have been conducted on SDB and cogni-
tive impairment.
15-17
These community-dwelling samples of-
ten include individuals with milder SDB, as opposed to those
examined in case-control studies. Some of these studies sug-
gested that SDB was associated with increased risk of demen-
tia or impairment across different cognitive domains,
18-20
while
others found no association.
17,21
Owing to different study de-
signs and methods to assess SDB, it is difficult to draw con-
clusions on the consistency of the associations. Moreover, be-
cause each study has reported on specific domains using
different scales, it is unclear if SDB has differential effects on
cognitive domains. Therefore, a meta-analytic approach is par-
ticularly useful for synthesizing these studies and elucidat-
ing pooled estimates for the effects of SDB on risk of cogni-
tive impairment as well as effects across different cognitive
domains. Given the high prevalence of cognitive impairment
in elderly persons and its significant consequences,
22,23
it is
critical to explore the role of SDB as a modifiable risk factor.
Methods
Search Strategy and Study Selection
We searched for articles published before January 2017 using
electronic databases, including PubMed, EMBASE, and
PsychINFO, and hand searched the reference lists of identi-
fied articles. Studies were identified using the search terms
“(sleep-disordered breathing OR sleep apnea OR obstructive
sleep apnea) AND (cognition OR cognitive function OR cogni-
tive decline OR dementia OR Alzheimer’s OR cognitive impair-
ment).” The search was restricted to articles published in
English. Studies were included if they (1) were original ar-
ticles published in a peer-reviewed journal; (2) used a cross-
sectional or prospective cohort design; (3) were conducted in
population-based samples (N ≥ 200; mean age ≥40 years);
(4) defined SDB by apnea-hypopnea index (AHI) or clinical di-
agnosis by International Classification of Diseases, Ninth Re-
vision (ICD-9) codes; (5) incorporated outcomes on Alzhei-
mer disease (AD), dementia risk, or cognitive impairment, as
defined by validated cognitive tests; (6) reported effect esti-
mates appropriate for the pooled analysis of effect sizes (eg,
odds ratios [ORs], hazard ratios, mean differences, or stan-
dardized mean differences [SMDs] in cognitive test scores) or
other types of estimates (eg, correlation or regression coeffi-
cient) that could be converted to the above forms; and (7) pre-
sented results adjusted for covariates (at least by age, sex, and
education). Studies were excluded if they (1) were case re-
ports, abstracts, reviews, or meta-analyses; (2) were con-
ducted in clinical populations; (3) used case-control design;
(4) used self-reported SDB; or (5) reported the prevalence of
SDB rather than studying SDB as a risk factor.
Data Extraction& Cognitive Outcomes
The eligibility of the studies to be included in the analysis was
determined and data were extracted independently by 2 in-
vestigators (Y.L. and C.T.M.). If multiple articles were pub-
lished from the same cohort reporting on the same cognitive
outcomes, we included only the one with the most complete
details; if multiple articles from the same cohort had differ-
ent study designs or if they reported on different cognitive out-
comes, we included each of these articles separately in the
analysis. Differences in data extraction between the extrac-
tors were resolved by consensus discussion and consultation
with a third investigator (K.Y.).
Because most prospective studies reported the OR or haz-
ard ratio for cognitive impairment,
15,18,24-26
risk ratio esti-
mates were extracted from these studies. To quantify the as-
sociation between SDB and different cognitive domains, we
extracted the adjusted cognitive test scores from the cross-
sectional studies.
17,27-30
We also obtained adjusted estimates
from Nikodemova et al
31
and Hrubos-Strøm et al
32
by contact-
ing the study authors. To be included in the pooled analysis,
a cognitive domain has to be represented by more than 3 stud-
ies; thus, we focused on 3 cognitive domains: global func-
tion, delayed memory (unless the study only assessed imme-
diate memory), and executive function. These domains are also
particularly important in the context of aging and develop-
ment of AD. The cognitive tests included from each study are
summarized in Table 1 and Table 2.
Definition of SDB
We included studies that used AHI or ICD-9codestodefine SDB.
Apnea-hypopnea index is the average number of apnea and hy-
popnea events per hour of sleep. In general, hypopnea is de-
fined as a discernible reduction in the airflow followed by at least
a 4% reduction in oxyhemoglobin saturation (AHI4%), at least
Key Points
Question What are the effects of sleep-disordered breathing
(SDB) on cognitive function and risk of cognitive impairment?
Findings In this systematic review meta-analysis that included
more than 4 million participants, those with SDB were 26% more
likely to develop cognitive impairment than those without SDB.
They also had slightly worse performance in executive function
but not in global cognition or memory.
Meaning Sleep-disordered breathing may be an important
modifiable risk factor for dementia and other cognitive
impairment; future studies are needed to examine if treatment
of SDB might reduce risk of cognitive impairment.
Research Original Investigation Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment
E2 JAMA Neurology Published online August 28, 2017 (Reprinted) jamaneurology.com
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a 3% reduction (AHI3%), or an event-related arousal (AHI3a).
Because there was a mixed use of these definitions in the in-
cluded studies, we first presented narrative description of the
definitions, and for the main analysis, we pooled the estimates
by AHI less than 15 and 15 or greater to be consistent with the
most commonly used cutoff
33
and to provide a most general-
izable categorization. For studies that havefurther broken down
these 2 categories,
17,25,27-29,32
we calculated a weighted mean
for AHI less than 15 and 15 or greater. For other studies
16,29,30
that did not provide sufficient information for analysis by this
cutoff, we contacted study authors or used other literature to
obtain necessary information for the calculation.
Statistical Analysis
We pooled risk ratios to summarize the prospective relation-
ship between SDB and cognitive impairment. One prospec-
tive study
17
reported the changes in z scores of 3 cognitive tests
that were strongly associated with AD or vascular dementia;
we converted the mean z scores of these tests into a single risk
ratio using the online meta-analysis calculator (David B. Wil-
son, PhD; http://www.campbellcollaboration.org/escalc/html
/EffectSizeCalculator-OR5.php).
For cross-sectional studies, we calculated SMD in cogni-
tive test scores by SDB status. In cases where a higher score
indicated worse cognition, we multiplied the score by −1 so that
high scores indicated better performance across all tests. One
study
34
only reported the OR, and this was converted to
Cohen d using the formula SMD = log(OR) × 兹3 / π. For one
study
29
where neither the SDs nor the 95% CIs were reported,
we used the SD of the same test from another previous study.
21
To estimate the pooled SMD for each cognitive domain, we first
calculated a summary Hedges g estimate for each domain from
each individual source study. This step ensures that multiple
relevant tests within each source study were all considered in
the analysis without being overrepresented in the pooled analy-
sis. All effect estimates were then pooled using a weighted ran-
dom-effects model.
We tested between-study heterogeneity using I
2
statistics
35
and used Egger test and funnel plot asymmetry to evaluate
publication bias.
36
All tests were 2-tailed. Sensitivity analysis
was conducted by excluding the studies that introduced sig-
nificant heterogeneity to the analysis on each cognitive out-
come. The quality of the included studies was evaluated in-
dependently by 2 investigators (Y.L. and C.T.M.) using the
Newcastle-Ottawa Quality Assessment Scale.
37
Our study ad-
heres to the Preferred Reporting Items for Systematic Re-
views and Meta-Analyses (PRISMA) guidelines
38
and the Meta-
analysis of Observational Studies in Epidemiology (MOOSE)
checklist.
39
All statistical analysis was performed using Re-
view Manager Software version 5 (Cochrane Collaboration).
Significance was set at P < .05.
Results
Literature Search and Study Characteristics
We identified a total of 3527 articles, including 1347 articles
from PubMed, 359 from PsychINFO, and 1821 from EMBASE.
Table 1. Summary of Prospective Studies on Sleep-Disordered Breathing and Risk of Cognitive Impairment
Source Total No. (% Men) Cohort; Country Age (Baseline), y Definition of Sleep Apnea Cognitive Outcome Adjusted Variables
NOS
Score
Lutsey et al,
17
2016
966 (48.6) ARIC; United States Mean (SD), 61.3 (5.0) AHI4%
(<5/5-14.9/15-29.9/≥30)
Decline in global cognition
(average of scores in DWR,
Word Fluency, and DSST)
Age, sex, field center, education level, alcohol
intake, smoking, physical activity, presence of
APOE4, BMI, CRP level, and CVD comorbidities
8
Blackwell et al,
15
2015
2636 (100) MrOS; United States Mean (SD), 76.0 (5.3) AHI3% (<15/>15) Decline in global cognition
(3MS score)
Age, site, race/ethnicity, BMI, education level,
depressive symptoms, CVD comorbidities,
Parkinson disease, IADL, benzodiazepine use,
antidepressant use, self-reported health,
physical activity, alcohol intake, and smoking
8
Martin et al,
25
2015
559 (39.7) Synapse; France Mean (SD), 66.9 (0.9) AHI3% (<15/15-30/>30) Decline in attention (Trail
Making Test A, Stroop
Color-Word Test, and WAIS-III)
Age, sex, education level, follow-up length,
BMI, ESS score, CVD comorbidities, anxiety, and
depression
9
Yaffe et al,
26
2015
200 000 (100) VA health medical record;
United States
≥55 Clinical diagnosis Risk of dementia Age, CVD comorbidities, obesity, depression,
income, and education level
9
Chang et al,
24
2013
8484 (59.3) Longitudinal health insurance
database; Taiwan
≥40 Clinical diagnosis Risk of dementia Age, sex, CVD comorbidities, urbanization level,
and income
9
Yaffe et al,
18
2011
298 (0) SOF; United States Mean (SD), 82.3 (3.2) AHI3% (<15/≥15) Risk of mild cognitive
impairment or dementia
Age, race/ethnicity, BMI, education level,
smoking, CVD comorbidities, antidepressant
use, benzodiazepine use, non-benzodiazepine,
and anxiolytics use
9
Abbreviations: 3MS, Modified Mini-Mental State Examination; AHI, apnea-hypopnea index; ARIC, Atherosclerosis
Risk in Communities Study; BMI, body mass index; CRP, C-reactive protein; CVD, cardiovascular diseases; DWR,
delayed word recall; DSST, Digit Symbol Substitution test; ESS, Excessive Sleepiness Scale; IADL, instrumental
activities of daily living; MrOS, Osteoporotic Fractures in Men Study; NOS, Newcastle-Ottawa Quality Scale;
SOF, Study of Osteoporotic Fractures; WAIS, Wechsler Adult Intelligence Scale.
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Table 2. Summary of Cross-sectional Studies on Sleep-Disordered Breathing and Performance in Different Cognitive Domains
Source
Total No.
(% Men) Cohort; Country Age, y Sleep Apnea Global Function Memory Executive Function Adjusted Variables
NOS
Score
Lutsey et al,
17
2016
a
966 (48.6) ARIC; United States Mean (SD),
61.3 (5.0)
AHI4%
(<5/5-14.9/15-29.9/≥30)
MMSE DWR/logical
memory test
Word
fluency/DSST/Trail
Making Test B
Age, sex, field center,
education level, alcohol
intake, smoking, physical
activity, presence of APOE4,
BMI, CRP, and CVD
comorbidities
8
Ramos et al,
16
2015
8059 (37.6) Hispanic/Latino
population; United
States
45-74 AHI3% (continuous) B-SEVLT SEVLT-recall Word fluency/DSST Age, sex, education level, CVD
comorbidities, depressive
symptoms, anxiety, smoking,
BMI, and field center
6
Dlugaj et al,
28
2014
1793 (51.3) Heinz Nixdorf Recall
Study; Germany
Mean (SD),
63.8 (7.5)
AHI (<15/15-29/≥30) NA Verbal memory Problem solving/speed
of processing
Age, sex, and education level 6
Nikodemova et al,
31
2013
755 (59.1) Wisconsin Sleep Cohort
Study; United States
Mean, 53.9 AHI4% (<5/5-14/≥15) NA AVLT Trail Making Test
B/symbol digit
modalities test/COWT
Age, sex, education level, and
BMI
6
Hrubos-Strøm
et al,
32
2012
290 (55.9) Akershus Sleep Apnea
Project; Norway
Mean (SD),
48.2 (11.2)
AHI4% (<15/≥15) NA AVLT
b
Stroop test Age, sex, and education level 6
Blackwell et al,
27
2011
2909 (100) MrOS; United States Mean (SD),
76 (6)
AHI3%
(<5/5-14/15-29/≥30)
3MS NA Trail Making Test B Age, race/ethnicity, clinic,
BMI, IADL, CVD comorbidities,
antidepressant use,
benzodiazepine use,
depression, education level,
alcohol use, smoking, physical
activity, and self-reported
health
7
Spira et al,
30
2008
448 (0) SOF; United States Mean (SD),
82.8 (3.4)
AHI3% (<30/≥30) MMSE NA Trail Making Test B Age, education level, and SSRI
use
6
Sharafkhaneh
et al,
34
2005
4 060 504 (83.9) VA health medical
record; United States
Mean (SD),
59.0 (15.5)
Clinical diagnosis Dementia
prevalence
NA NA Age, sex, and race/ethnicity 6
Foley et al,
29
2003
718 (100) Honolulu-Asia Aging
study; United States
79-97 AHI4%
(<5/5-14/15-29/≥30)
MMSE NA NA Age, education level, and
marital status
6
Abbreviations: AHI, apnea-hypopnea index; ARIC, Atherosclerosis Risk in Communities Study; AVLT, Auditory
Verbal Listening Test; BMI, body mass index; B-SEVLT, Brief-Spanish English Verbal Learning Test;
COWT, Controlled Oral Word Test; CRP, C-reactive protein; CVD, cardiovascular diseases; DWR, delayed word
recall; DSST, Digit Symbol Substitution test; IADL, instrumental activities of daily living; MMSE, Mini-Mental State
Examination; MrOS, Osteoporotic Fractures in Men Study; NA, not applicable; NOS, Newcastle-Ottawa Quality
Scale; SOF, Study of Osteoporotic Fractures; SSRI, selective serotonin reuptake inhibitor.
a
The cross-sectional analysis from this prospective study is assessed.
b
Immediate memory; all other memory tests were based on delayed recall.
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