PULMONARY PERSPECTIVE

Obstructive Sleep Apnea and the Risk of Cognitive Decline in

Older Adults
Nadia Gosselin1,2,3, Andrée-Ann Baril1,2,3, Ricardo S. Osorio4,5, Marta Kaminska3,6, and Julie Carrier1,2,3
1
Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, Canada; 2Université de Montréal,
Montreal, Canada; 3Canadian Sleep and Circadian Network, Canada; 4Center for Brain Health, New York University Langone Medical
Center, Manhattan, New York; 5Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York; and 6Respiratory
Epidemiology and Clinical Research Unit, Respiratory Division and Sleep Laboratory, Department of Medicine, McGill University Health
Center, Montreal, Canada

Insufficient or poor-quality sleep affects the will refuse it (5) and more than 33% will sex, APOE4 [apolipoprotein e4 allele],
immune system, weight management, not use it in the long term (6). These body mass index, years of education,
glucose metabolism, cardiovascular and statistics suggest that many individuals who cardiovascular disease, or depression).
cerebrovascular health, cognition, work could benefit from treatment to possibly In the older population, the link
productivity, psychological well-being, and prevent neurodegeneration remain between OSA and risk of cognitive decline
public safety. Recent findings indicate that untreated. To improve treatment decision or dementia has only recently been
sleep participates in the production and making and to increase adherence, we need documented in prospective cohorts. A study
clearance of brain metabolic products (1) to clearly depict the impact of OSA and its published in 2011 showed that among
including those involved in dementia treatment on the aging brain. This 298 women aged 82.3 years on average, a
pathogenesis (2). How these new Pulmonary Perspective presents the most higher risk of developing mild cognitive
discoveries from animal models provide recent findings on the neurocognitive impairment (MCI) or dementia at the 4.7-
information on the impact of sleep consequences of OSA in older adults, a year follow-up was associated with OSA,
disorders on brain health is a significant research field that has shown major growth and linked to severity of hypoxia (9). More
question. in the past few years. recently, a study performed with the
The harmful effect of disturbed sleep on Alzheimer’s Disease Neuroimaging
brain health is particularly important for Initiative cohort showed that OSA was
older adults presenting obstructive sleep Epidemiological Evidence associated with an earlier age of progression
apnea (OSA). OSA causes not only sleep Linking OSA to Cognitive to MCI or Alzheimer’s disease (AD) (10).
fragmentation but also intermittent Decline However, a study using the PROOF-
hypoxia, which may affect both brain SYNAPSE cohort showed only small
structure and function. OSA is common, Recent meta-reviews have confirmed that longitudinal changes in selected cognitive
particularly after the age of 65 years, when it OSA in middle-aged adults is associated functions (11). This weak link between
has an estimated prevalence of at least 20% with deficits in multiple cognitive domains. OSA and cognitive impairment was also the
(3). Despite the increasing awareness of Attention, vigilance, episodic memory, conclusion drawn in one recent systematic
OSA and its consequences, one recent study working memory, and executive function review and meta-analysis (12). In another
showed that only 8% of older adults at high are the cognitive domains most commonly meta-analysis of six prospective studies that
risk of OSA are tested with home or in- impaired, whereas psychomotor abilities, included 212,943 participants more than
laboratory sleep studies; when at risk adults language, and visuospatial function remain 40 years of age, the authors concluded that
were investigated, OSA was confirmed less systematically affected (7, 8). Studies adults with OSA were 26% more likely to
in 94% of the cases (4). When OSA is show, however, an important heterogeneity develop significant cognitive decline or
diagnosed in older adults, clinicians face a in results due to differences in OSA dementia at the 3- to 15-year follow-up (8).
dilemma as to whether patients with the definitions (e.g., self-reported vs. objectively With these new findings in mind, clinicians
most common forms of mild to moderate confirmed OSA, apnea–hypopnea index now face the challenge of correctly
OSA and/or those without daytime cutoffs, differences in hypopnea criteria), identifying patients at greater risk of
sleepiness or comorbid health problems neuropsychological tests (screening tests vs. cognitive decline, particularly in those
should be treated or not. Even when comprehensive assessments), and variables without daytime symptoms in whom
treatment is recommended, 30% of adults adjusted for in statistical analyses (e.g., age, treatment is not systematically proposed.

( Received in original form January 31, 2018; accepted in final form August 15, 2018 )
Correspondence and requests for reprints should be addressed to Nadia Gosselin, Ph.D., Center for Advanced Research in Sleep Medicine, Hôpital du
Sacré-Cœur de Montréal, 5400 boulevard Gouin Ouest, local J-5135, Montreal, QC, H4J 1C5 Canada. E-mail: nadia.gosselin@umontreal.ca.
Am J Respir Crit Care Med Vol 199, Iss 2, pp 142–148, Jan 15, 2019
Copyright © 2019 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201801-0204PP on August 16, 2018
Internet address: www.atsjournals.org

142 American Journal of Respiratory and Critical Care Medicine Volume 199 Number 2 | January 15 2019
PULMONARY PERSPECTIVE

Candidate Mechanisms That REM sleep (19), and possible changes in (CPAP) had normal Ab42 and total
Could Link OSA to Cognitive sleep spindles (20) and K-complexes (21). tau/Ab42 ratio levels. These CSF findings
Decline Although hypothetical, these repetitive suggest an accumulation of amyloid
sleep architecture alterations may lead not plaques and tau protein in the brain. A
Why and how OSA is linked to dementia are only to next-day neurocognitive deficits, similar study performed in community-
questions that are generating intensive but also to changes in brain structure dwelling elderly adults confirmed these
research efforts. Untreated OSA can (e.g., alteration of white and gray matter, findings by showing that the severity
make the brain more vulnerable to changes in cerebral networks) due to of OSA was associated with 2-year
neurodegenerative processes by gradually chronic impairment of sleep-dependent longitudinal decreases in CSF Ab42 (25).
altering its structure and functioning (13). neurogenesis and synaptic plasticity. Furthermore, in a recent study, neuronally
Figure 1 presents candidate mechanisms Consequently, when a neurodegenerative derived proteins (CSF Ab40, Ab42,
that could explain the increased risk of process occurs, the apneic brain could be neurogranin, and VILIP-1 [visinin-like
abnormal cognitive decline in older adults more vulnerable to the clinical expression protein-1]) were lower in a group of 10
with OSA. One potential mechanism relates of dementia (22). patients with OSA compared with 31
to the crucial role of sleep in optimal There are also recent studies that link control subjects (26).
cognitive functioning. In fact, studies OSA to AD biomarkers, namely Ab42 and In terms of mechanism, hypoxia, sleep
consistently show that sleep continuity, tau proteins, that accumulate in the form disruption, and impaired SWS in OSA could
slow-wave sleep (SWS), REM sleep, of plaques or tangles in the AD brain (23). all be responsible for accentuation of AD
K-complexes, and sleep spindles have In humans, a study performed in a sleep biomarkers. Animal models and a few
specific and essential roles in neurogenesis clinic reported lower cerebrospinal fluid human studies support a link between Ab
(14), synaptic plasticity (15), and next-day (CSF) Ab42 and higher total tau/Ab42 generation, production, and clearance in
vigilance (16), as well as in memory ratio levels in untreated individuals with association with disturbed sleep and
formation and consolidation (17, 18). OSA OSA than in those with treated hypoxia. More specifically, recent studies
is associated with major and chronic OSA and control subjects (24). In that suggest that sleep fragmentation and
changes in sleep characteristics, including study, patients with OSA treated with reduced SWS can increase Ab deposition
sleep fragmentation, decrease in SWS and continuous positive airway pressure (27). Interestingly, in a mouse model,

Obstructive sleep
apnea

Altered sleep macro- and microarchitecture (e.g., slow

Intermittent hypoxemia
waves, spindles, sleep fragmentation, REM sleep)

Systemic and brain response to hypoxemia (e.g., metabolic disturbances /

diabetes, oxidative stress, inflammation, hypertension, blood–brain barrier
dysfunction, brain edema)

Reduced neurogenesis, Changes in brain structure Accumulation of amyloid plaques

Small vessel disease,
synaptic plasticity, and (grey and white matter) and and hyperphosphorylated tau
microinfarcts, and stroke
cognitive function cerebral networks proteins in the brain

Abnormal cognitive
decline and dementia

Figure 1. Schematic representation of possible mechanisms linking obstructive sleep apnea to dementia. Obstructive sleep apnea leads to intermittent
hypoxemia and changes in sleep macro- and microarchitecture. Intermittent hypoxemia probably causes systemic and brain responses that include
metabolic disturbances/diabetes, oxidative stress, inflammation, hypertension, blood–brain barrier dysfunctions, and brain edema. These responses,
combined with the altered sleep macro- and microarchitecture, may lead to small-vessel disease, microinfarcts, strokes, reduced neurogenesis, reduced
synaptic plasticity, decreased cognitive functioning, changes in brain white and gray matter, changes in cerebral networks, and abnormal levels of
Alzheimer’s disease biomarkers, which can all be involved in abnormal cognitive decline and dementia. Mechanisms in yellow boxes/dashed rectangle
may all interact to create a vicious cycle; they also have the potential to alter sleep architecture and play a role in the systemic and brain responses to
hypoxemia.

Pulmonary Perspective 143

 PULMONARY PERSPECTIVE

chronic sleep deprivation doubled Ab norepinephrine supply that shows early showed that more severe OSA is associated
levels in the brain (28). Moreover, neurofibrillary tangle formation due to with increased rates of Ab deposition,
sleep is implicated in the clearance of aggregation of hyperphosphorylated tau using Pittsburgh compound B–positron
toxic proteins and metabolic waste protein in AD (36). Interestingly, this emission tomographic imaging in older
accumulated during wakefulness through region is involved in the control of the adults (25, 40). On the other hand, whether
interstitial space expansion during sleep, sleep–wake cycle. Hypoxemia possibly hypertrophy represents acute adaptive
which promotes fluid exchange with CSF affects regions involved in regulation of mechanisms such as edema or reactive
(1). Regarding this latter mechanistic the sleep–wake cycle (e.g., locus coeruleus gliosis in milder OSA forms is an
hypothesis, three potential mechanisms and dorsal raphe nucleus), creating interesting question that would need to
could be involved: 1) intrathoracic subsequent sleep disruption and then be addressed.
pressure swings from respiratory efforts contributing to more Ab accumulation Cerebral white matter is vulnerable to
against a closed airway that would impede (see Reference 37 for a more detailed hypoxia as well, and results from the
the glymphatic flow of metabolites discussion); this hypothesis needs further literature also underline the complex
from interstitial fluid to the CSF (29), investigation. changes in brain structure associated with
2) a reduction in the clearance of OSA. Rather than reporting the typical
subarachnoid CSF directly into dural patterns of diffusion associated with white
lymphatic channels due to increased How Brain Structure and matter loss, most studies using diffusion
venous pressure that is typically elevated Function Change in Older tensor imaging in young and middle-aged
in OSA, and 3) cerebral edema secondary Adults with OSA adults have found reduced diffusivities
to intermittent hypoxia that reduces along white matter tracks in OSA (41–43).
interstitial space expansion (30). Finally, Most neuroimaging studies on OSA have Reduced diffusivity suggests that an
several animal models showed that been performed in young and middle-aged ongoing brain response to OSA, such as
hypoxia could play an important role in adults. Whether these findings can be swelling or increased brain water content,
the Ab cascade via HIF-1a (hypoxia- generalized to an aged brain is unclear, prevents water movement. This pattern
inducible factor-1a), which increases the as neuroimaging studies with older adults of reduced diffusivities was previously
activity of various secretases (including have only just emerged. Neuroimaging observed in acute and/or preclinical
BACE1), leading to an elevated techniques allow indirect and large-scale stages of familial AD and stroke (44, 45).
production of Ab peptides (31). In measurements of neuroanatomical Whether these changes evolve into
addition to increased Ab generation, structures and their functioning. Given neuronal death still needs to be verified
hypoxia affects peptidases that degrade the complexity of changes that can occur with longitudinal studies.
Ab peptides, thus reducing Ab clearance. in response to OSA (e.g., cellular death, Regarding cerebral functioning,
Finally, hypoxia reduces the activity of edema, increase in brain water content, a systematic review that included six
the neuroprotective a-secretase, neuroinflammation, changes in cerebral studies of young and middle-aged adults
furthering the Ab cascade. perfusion, and increase in Ab deposition), reported reduced resting-state functional
Responses to upper airway obstruction heterogeneous results can be obtained connectivity within and between several
can also affect brain health with age. depending on the participants’ age, regions including the hippocampus,
In fact, apneas and hypopneas provoke severity of intermittent hypoxia and sleep the posterior cingulate, the medial
adaptive (e.g., ischemic preconditioning) fragmentation, clinical stages of dementia, prefrontal cortex, the medial temporal
but also maladaptive and potentially and so on. OSA may also lead to nonlinear lobe, the basal ganglia, the insula, and the
harmful responses (e.g., oxidative changes in brain structure and function cerebellum (46). In parallel, a functional
stress, inflammation, hypertension, due to phasic adaptive and maladaptive neuroimaging study in adults aged
dysautonomia, impaired glucose tolerance, responses. As an example, studies in young 55 years and older measured regional
and blood–brain barrier dysfunction) and middle-aged adults usually show gray cerebral blood flow using single-photon
that may damage cerebral cells and matter atrophy in patients with OSA as emission computed tomography and
organelles, and make neurons more compared with control subjects, and the showed that participants with severe OSA
susceptible to cellular death (32). Not parahippocampal and frontotemporal had hypoperfusion in sensorimotor areas
surprisingly, studies have shown that cortex are the brain regions most and the parietal lobes (47). Moreover,
severe OSA increases the risk of cerebral consistently affected (38). However, in a hypoperfusions in the parietal, temporal,
small-vessel disease (33) and stroke (34). study of adults aged 55–76 years, OSA and frontal lobes were associated with
In a postmortem study of 167 older severity was associated with gray matter higher levels of respiratory disturbances,
adults, hypoxemia measured on prior hypertrophy and higher cortical thickness daytime sleepiness, and obesity. Hence,
polysomnographic recordings was in frontal, parietal, and cingulate regions, as functional neuroimaging is sensitive to
associated with more brain microinfarcts well as in the amygdala (39). This pattern of changes associated with OSA. However,
at autopsy (35). When only hypoxemia gray matter hypertrophy and thickening in studies with elderly participants are
during REM sleep was considered in that middle-aged and older patients with OSA needed to verify whether anomalies
study, a significant association was also may be due to local increases in brain water observed in younger subjects are
found for gliosis and neuronal loss in content secondary to hypoxia, inflammation, applicable to the older population and are
the locus coeruleus. The locus coeruleus and/or with Ab deposition. In accordance predictive of a cognitive decline. In that
is a brainstem region responsible for with this hypothesis, recent studies context, longitudinal neuroimaging

144 American Journal of Respiratory and Critical Care Medicine Volume 199 Number 2 | January 15 2019
PULMONARY PERSPECTIVE

studies would allow clarification of the a neurodegenerative disease. According to a lack of studies on long-term adherence to
evolution of brain functional changes in recent meta-analysis, patients with AD have CPAP in older adults with dementia.
elderly individuals with OSA. a 50% chance of experiencing OSA after Moreover, it is not known whether
their dementia diagnosis (51). The authors strategies that improve compliance with
hypothesized that this high rate of OSA in CPAP in nondemented adults (e.g.,
How Treating OSA Impacts AD could be due to the possible role of feedback of compliance data) (63) are
the Aging Brain OSA in dementia pathogenesis. In a series also efficient in patients with AD. The
of pioneer studies by Ancoli-Israel and involvement of relatives is probably a
OSA treatment, such as CPAP, is effective colleagues, reduced daytime sleepiness and major factor in short- and long-term
for reducing hypopneic and apneic events. cognitive deficits, as well as improvement in CPAP adherence in this clinical
However, patients generally suffer from OSA sleep quality, were observed after treatment population.
for several years before being diagnosed and with CPAP in patients with AD (52–54).
treated. Whether CPAP treatment can slow Slower cognitive decline on the Mini
down, stop, or reverse neurodegenerative Mental State Examination was also Risk Factors and Prevention
processes potentially accentuated by OSA is a reported in another study of mild to of Cognitive Decline in the
crucial question, particularly for patients who moderate AD in patients with severe Context of OSA
start their treatment after the age of 65 years. OSA treated with CPAP compared with
Unfortunately, most published studies nontreated patients (55). These results Few studies have investigated whether some
investigating the effect of CPAP on brain support the hypothesis that OSA aggravates factors moderate, that is, reinforce or
health were performed among young and cognitive dysfunction when neurodegenerative weaken, the association between OSA
middle-aged patients. However, in a processes are already present and that severity and cognitive impairment. It is
randomized study of 33 patients with OSA CPAP can have a positive impact on possible that individual characteristics
aged 71.3 6 5.5 years, 3 months of CPAP cognitive functioning in the demented or comorbidities can make some older
improved short-term memory, working population. adults with OSA more or less at risk of
memory, selective attention, and executive This aggravation effect of OSA on developing dementia. For example, a 5-year
functions as well as functional connectivity cognition is not limited to patients with AD longitudinal cohort study of 7,547 men
in the right middle frontal gyrus (48). and is also common in patients with other showed that self-reported OSA was
More recently, preliminary evidence in a neurodegenerative conditions. For instance, associated with risk of dementia only in
nondemented cohort of elderly participants, OSA in nondemented patients with APOE4 noncarriers (64). However, the
involved in a study from the Alzheimer’s Parkinson’s disease (PD) increases reverse result was found in three cross-
Disease Neuroimaging Initiative, showed that sleepiness and reduces global cognition sectional studies, where the association
CPAP treatment delayed the age of MCI (56). Moreover, treatment of OSA was between OSA and impaired cognition
onset by approximately 10 years (72 vs. 82 yr associated with stabilization of motor was stronger in APOE4 carriers than in
old), whereas age at MCI onset in participants function (57) and improvement in sleep noncarriers (65–67).
reporting treated OSA was similar to the non- quality, sleepiness (58), and cognitive
OSA group (10). A recent case study of a function, particularly in those with reduced
patient with OSA and subjective cognitive function at baseline (59), although a shorter
Future Directions
impairment showed that 1 year of CPAP trial found no change in cognition (60).
Research on the long-term neurocognitive
treatment normalized the CSF Ab42 and t- Another important question is whether
consequences of OSA is just emerging, but
tau/Ab42 ratio levels as well as the cognitive OSA has an impact on the progression of
recent studies have transformed this field by
complaints (49), suggesting that OSA might motor dysfunction and the overall
moving the focus from middle-aged to older
be a reversible risk factor for dementia. neurodegenerative process of PD. A recent
adults. Still, few longitudinal studies with
However, a 12-month randomized trial study suggests that OSA increases the risk
objective monitoring for OSA have been
showed no effect of CPAP on cognitive of developing PD in women (61). Hence,
published. This type of study design is
function in adults aged 65 and older, OSA might be a risk factor for cognitive
necessary to reveal how cognitive functioning
despite improvement in sleepiness (50). decline in neurodegenerative disorders,
in the elderly evolves in the context of
This absence of changes in cognitive function with the predominant pathology and
OSA.
could be attributed to a ceiling effect, as clinical manifestations depending on
the participants had normal cognitive predisposing factors. CPAP therapy is d One of the first lines of research could
performance at baseline. However, negative challenging in patients with a be to identify vulnerable patients with
results from this study should be interpreted neurodegenerative disease or dementia due OSA who could benefit the most from
with caution due to the overall low compliance to anxiety, nocturia, insomnia, and treatment. In addition, whether OSA in
of this cohort. More studies are urgently cognitive and motor impairment affecting patients with mild to moderate disease,
needed to confirm these preliminary the ability to wear the mask, but studies who are asymptomatic or present mild
findings and expand our knowledge have shown that it is feasible (52–54, 56). In daytime symptoms, could lead to
regarding the effect of OSA treatment one study, the presence of depressive dementia in the long term is not clear.
on neurodegeneration in the elderly. symptoms in patients with OSA and mild We need to characterize genetic, sleep,
Another important issue relates to the to moderate AD was associated with worse and/or respiratory characteristics that
effect of OSA in patients already presenting CPAP adherence (62). There is, however, a put patients at greater risk of dementia.

Pulmonary Perspective 145

 PULMONARY PERSPECTIVE

For clinical purposes, we have to validate reduce Ab deposition, as previously CPAP use and duration to be effective
screening tests and biomarkers (e.g., described in nonapneic participants (71). on cognitive function. Whether OSA
genetics, blood biomarkers, and d Another line of research is to clarify the treatment can stop or reverse the
neuroimaging) that could identify mechanistic processes that link OSA to cognitive decline of older adults
vulnerable patients. dementia, to identify novel targets for presenting with MCI needs to be
d There is a need to study how factors that intervention. Preliminary evidence investigated.
are already known to affect the clinical suggests that cognitive decline in OSA d It will be important to evaluate the
expression of dementia, for example, age, may share similar mechanisms with therapeutic and economic costs and
sex, hypertension, hypercholesterolemia, those already described in AD benefits of CPAP in older people,
diabetes, smoking, depression, metabolic (i.e., aggregation of Ab and tau in the particularly in those with mild or
syndrome, and obesity (68), influence the brain) or vascular dementia. These moderate OSA, and include a
evolution of cognitive decline in adults results should be confirmed in particular consideration of cognitive
with OSA. Considering that OSA is longitudinal studies. In the same decline in the cost-effectiveness
frequently caused by obesity and is a risk manner, whether brain structure and analysis.
factor for hypertension, diabetes, and function anomalies in nondemented d The long-term neurocognitive
depression (69), studying their additive older adults with OSA evolve into consequences of untreated OSA are
or interacting roles could help identify dementia is unknown. Testing generally not considered in treatment
those adults more vulnerable to the mechanistic hypotheses explaining the decision making. It is noteworthy that we
neurocognitive effects of OSA. impact of OSA on human cerebral now have sufficient evidence supporting
d We also need to understand how physiology and function warrants the use the role of sleep quality and duration in
lifestyle (e.g., high education or of the most advanced neuroimaging neurocognitive health to make sustained
cognitive reserve, healthy diet, physical methodologies. efforts to translate this knowledge.
exercise, social activities) could prevent d Another important aspect is to Although this latter point is not a
the deleterious effects of OSA on brain determine the long-term effects of research objective, it should be
health. For example, exercise training OSA treatment on neurocognitive considered a priority to transform
has been described as having positive health. Several variables need clinical practice and public health
effects on OSA severity in sedentary to be considered, including the age policies. n
overweight/obese young and middle- at OSA diagnosis and age when
aged adults (70). Moreover, we need treatment was started. We need to Author disclosures are available with the text
to verify whether physical activity can determine thresholds for minimum of this article at www.atsjournals.org.

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148 American Journal of Respiratory and Critical Care Medicine Volume 199 Number 2 | January 15 2019