Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009
reported to be greater than 40% in those who are institution-
alized.1 Untreated OSA itself can have deleterious effects on
cognition and daytime functioning,2-4 and may exacerbate the
primary cognitive and functional deficits associated with AD.5-
7 The most effective treatment of OSA is continuous positive
airway pressure (CPAP).8 Our laboratory recently showed
that, in a 6-week randomized placebo controlled clinical trial
(RCT) of CPAP in patients with mild-moderate AD and OSA,
CPAP improved OSA, objective sleep parameters, and daytime
sleepiness, and resulted in modest improvements in measures
of cognitive functioning.9-11 Some participants were so pleased
with the effects of CPAP that they purchased their own CPAP
machines in order to continue treatment after completing the
6-week RCT. Although long-term follow-up evaluation was not
bstructive sleep apnea (OSA) is common among patients
with Alzheimer’s disease (AD), with prevalence rates
part of the original study design, the continued use of CPAP by
some patients presented the opportunity to explore the potential
benefits of prolonged CPAP use in AD patients with OSA and
to ask the question whether the positive effects on sleep, mood
and cognition were maintained with sustained CPAP use.
Five patients who continued CPAP (CPAP+), and five pa-
tients who chose to discontinue CPAP (CPAP−) at the end of
the 6-week RCT were included in these analyses. Sleep and
mood of the patients’ caregivers were also evaluated. Details of
the RCT are described in Ancoli-Israel et al.,9 including inclu-
sion/exclusion criteria; briefly, all participants (n = 52) in the
RCT had a diagnosis of AD, a Mini Mental Status Examination
(MMSE)12 score ≥ 18, an available caregiver, and an apnea-hy-
popnea index (AHI; number of apneas plus hypopneas per hour
of sleep) ≥ 10 (based on polysomnography). All participants
and caregivers signed consent forms for the initial RCT and for
this follow-up visit, which were approved by the University of
California San Diego Human Research Protections Program.
Sustained Use of CPAP Slows Deterioration of Cognition, Sleep, and Mood in Patients
with Alzheimer’s Disease and Obstructive Sleep Apnea: A Preliminary Study
Jana R. Cooke, M.D.1,5; Liat Ayalon, Ph.D.2; Barton W. Palmer, Ph.D.2; Jose S. Loredo, M.D.1,5; Jody Corey-Bloom, M.D., Ph.D.4,5; Loki Natarajan, Ph.D.3;
Lianqi Liu, M.D.2; Sonia Ancoli-Israel, Ph.D.2
1Department of Medicine, 2Department of Psychiatry, 3Department of Family and Preventative Medicine, and 4Department of Neurosciences,
University of California, San Diego, CA; 5Veterans Affairs San Diego Healthcare System, San Diego, CA
Submitted for publication February, 2009
Accepted for publication February, 2009
Address correspondence to: Sonia Ancoli-Israel, Ph.D., University of Cali-
fornia, San Diego, Department of Psychiatry, 9500 Gilman Dr. #0733, La
Jolla, CA 92093-0733; Tel: (858) 822-7710; Fax: (858) 822-7712; E-mail:
introduction: Obstructive sleep apnea (OSA) is common among pa-
tients with Alzheimer’s disease (AD). Untreated OSA exacerbates the
cognitive and functional deficits. Continuous positive airway pressure
(CPAP) has recently been shown to have beneficial effects on cogni-
tion in AD. Little attention has focused on the long-term benefits of
CPAP in these patients.
Methods: This was an exploratory study of sustained CPAP use
(mean use = 13.3 months, SD = 5.2) among a subset of participants
from an initial 6-week randomized clinical trial (RCT) of CPAP in pa-
tients with mild to moderate AD. Follow-up included 5 patients who
continued CPAP (CPAP+) after completion of the RCT and 5 patients
who discontinued CPAP (CPAP−), matched by time of completion of
the initial study. A neuropsychological test battery and sleep/mood
questionnaires were administered and effect sizes were calculated.
Results: Even with a small sample size, sustained CPAP use resulted
in moderate-to-large effect sizes. Compared to the CPAP− group, the
CPAP+ group showed less cognitive decline with sustained CPAP use,
stabilization of depressive symptoms and daytime somnolence, and
significant improvement in subjective sleep quality. Caregivers of the
CPAP+ group also reported that their own sleep was better when com-
pared to the final RCT visit and that their patients psychopathological
behavior was improved.
conclusion: The results of this preliminary study raise the possibil-
ity that sustained, long-term CPAP treatment for patients with AD and
OSA may result in lasting improvements in sleep and mood as well
as a slowing of cognitive deterioration. Prospective randomized con-
trolled research trials evaluating these hypotheses are needed.
Keywords: CPAP, apnea, dementia, cognition
citation: Cooke JR; Ayalon L; Palmer BW; Loredo JS; Corey-Bloom
J; Natarajan L; Liu L; Ancoli-Israel S. Sustained use of CPAP slows
deterioration of cognition, sleep, and mood in patients with Alzheimer’s
disease and obstructive sleep apnea: a preliminary study. J Clin Sleep
Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009
JR Cooke, L Ayalon, BW Palmer et al
Methods and Measures
In 2004, 3 years into the RCT study, a telephone interview
was conducted with all participants who had already com-
pleted the RCT to determine if any had chosen to continue
CPAP use. Those study participants who reported continued
CPAP use were asked if they would be interested in taking
part in the follow-up study. All follow-up assessments were
conducted in the home and each participant completed the
same neuropsychological test battery (described below) as in
the RCT. Both the participant and caregiver also completed
the same sleep/mood questionnaires administered during the
initial RCT study. As each participant carried the diagnosis
of AD, caregivers assisted participants with these question-
naires. Each participant in the CPAP+ group was matched by
time of completion of the initial RCT to participants who had
chosen to discontinue CPAP use.
The procedure for overnight in-home polysomnography (PSG)
was previously described,13 and the same procedure was repeated
for this follow-up evaluation for the CPAP+ group. Repeat PSG
was not conducted in the CPAP− group, as most were not willing
to repeat the sleep recording. The total number of apneas (defined
as an 80% airflow decrease from baseline for ≥ 10 sec) and hy-
popneas (defined as a 30% to 80% airflow decrease ≥ 10 sec as-
sociated with a desaturation ≥ 3% or with an arousal) were scored
and divided by the total sleep time to calculate the AHI.
Patients and caregivers completed the Pittsburgh Sleep Qual-
ity Index (PSQI),14 the Epworth Sleepiness Scale (ESS),15 the
Functional Outcomes of Sleep Questionnaire (FOSQ),16 and the
Cornell Scale for Depression (CSD) in Dementia.17 Caregivers
also completed the Neuropsychiatric Inventory (NPI).18
Participants completed the same neuropsychological test
battery from the RCT, described in detail in Ancoli-Israel et al.9
Briefly, tests chosen evaluated cognitive abilities of particular
relevance to AD (learning/ memory), to OSA-related hypoxia
and/or its treatment (learning/memory, and “frontal/ executive
skills”), to sleepiness/ sleep disturbance (attention, vigilance),
as well as to normal aging (mental processing speed). The test
battery included: (1) Global cognition (overall score from the
Mattis’ Dementia Rating Scale [DRS])19; (2) Basic attention
and vigilance (total correct on the Digit Cancellation task)20;
(3) Psychomotor speed (time to complete [seconds] the Trail
Making Test Parts A,21 raw scores from the Wechsler Adult In-
telligence Scale–Third Edition [WAIS-III],22 and Digit Symbol
and Symbol Search subtests); (4) Verbal episodic memory (total
recall on learning trials 1 through 3 from the Hopkins Verbal
Learning Test–Revised [HVLT-R])23,24; and (5) tests sensitive
to various aspects of executive functioning (Trail Making Part
B [seconds to complete],21 conceptual level responses from the
64-card version of the Wisconsin Card Sorting Test [WCST-
64],25,26 total words completed on the Color-Word Interference
trial of the Stroop Color and Word Test,27 and total correct words
generated on the Letter fluency [FAS] test and on the Category
[Animals] Fluency test).28,29
Due to the small sample size, effect sizes were used to quan-
tify differences in sleep, mood, and neuropsychological mea-
sures between the CPAP+ and CPAP− groups. The effect-size
for each measure was computed as standardized mean differ-
ences in change score between final RCT and follow-up visit,
namely, (d1-d2)/δp (d1 and d2 are the change scores in the CPAP+
and CPAP− groups respectively, and δp is the pooled standard
deviation of the change score). For the sake of completeness,
despite the small sample size, we also conducted 2 sample Stu-
dent’s t-test and Mann-Whitney test for the mean change scores
(between the final RCT and follow-up visits). For the DRS
measure which was only given at the initial RCT study entry,
the Student’s t-test and Mann-Whitney test were performed on
the RCT baseline and the follow-up visit scores.
Participants: Ten participants (7 men and 3 women) and 9
caregivers (one patient had moved into an assisted living facil-
ity and therefore that caregiver was not included) participated
in the follow-up evaluation. The mean follow-up time from
completing the RCT was 13.3 months (SD = 5.2, range = 6−21
months). There were no meaningful differences between the 2
groups on any demographic measures at follow-up. Participants
had a mean age of 75.7 years (SD = 5.9, range = 65−84), had
moderate dementia (mean follow-up MMSE = 22.6, SD = 4.5,
range = 16−27), were mildly overweight (mean BMI = 25.9,
SD = 3.1, range = 21−31) and on average had ≥ 14 years of
education (mean = 14.6 years, SD = 2.7, range = 12−20 years).
The majority of patients (9 of 10) were Caucasian. At follow-
up, the CPAP+ group had a mean AHI of 1.6 (SD = 2.3, range =
0.2–5.7) while using CPAP.
Follow-Up Questionnaire Results: At the end of the RCT, the
participants had comparable scores for sleep and mood. Even
with the study’s small sample size, there were several notewor-
As can be seen in Figure 1, the CPAP+ group’s depressive
symptoms (based on CSD), daytime sleepiness (based on ESS)
and subjective sleep quality (based on PSQI) either showed less
deterioration or improved from the end of the RCT to follow-up
compared to the CPAP− group.
There were no differences between groups in the amount of
change in either the FOSQ (effect size = −0.2) or the MMSE
(effect size = 0.1).
Follow-Up Neuropsychological Results: Similar to the sleep/
mood scores, at the end of the RCT, the participants had com-
parable scores on the individual tests in the neuropsychological
As with the sleep mood questionnaires, there were some no-
table results. As assessed by the DRS, there was a moderate
effect on global cognition with the CPAP+ group having less
deterioration when compared to the CPAP− group (effect size
In addition, as shown in Table 1, the CPAP+ group showed
evidence of improvement in executive functioning as assessed
by WCST (effect size = 0.7), Stroop Color-Word Score (effect
size = −0.8), Trails B (effect size = −0.3) and FAS Total Letter
Score (effect size = −0.7) while the CPAP− group appeared to
deteriorate on these tests. Sustained CPAP use also appeared to
have positive effects on psychomotor speed (WAIS effect size =
−1.9; Trails A effect size = −0.5) with the CPAP+ group show-
Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009
ing evidence of improvement while the CPAP− group appeared
Caregivers: Caregivers of the CPAP+ group reported stabi-
lization of the patients’ psychopathology symptoms (based on
the caregivers’ scoring of the NPI) while the CPAP- caregiv-
ers noted worsening symptoms (effect size = −1.5, p = 0.07 by
Mann-Whitney test). Compared to the caregivers of the CPAP−
group, the CPAP+ caregivers’ subjective sleep quality based on
the PSQI remained stable, while the caregivers of the CPAP−
group showed evidence of deterioration (effect size = −1.3, p =
0.02 by Mann-Whitney test). In addition, there were moderate
effects in the caregivers own depression ratings (CSD effect
size = −0.3) and their own quality of life ratings (FOSQ effect
size = 0.5) scores.
The results of this study suggested that continued use of
CPAP may be associated with some sustained benefits in sleep,
mood, and cognitive functioning. The CPAP+ group either
remained stable or showed improvement (i.e., changed in the
direction of improvement) on almost all measures while the
CPAP− group continued to deteriorate, as would be expected
over time in patients with AD. The sustained use of CPAP also
appeared to benefit these patients’ caregivers who reported that
their own sleep quality improved, their own mood remained
stable, and the patients’ psychopathology was stabilized.
This study focused on the sustained effects of CPAP use
and did not include any analysis of changes from baseline (i.e.,
pre-CPAP treatment) to follow-up, as each participant received
CPAP treatment during the initial RCT and showed similar ben-
efits on all measures. Rather the study focused on the long-term
effect of CPAP use vs. discontinuation of treatment.
To our knowledge, there have been no published reports de-
scribing the pattern of cognitive functioning among AD patients
using CPAP over several months. Likewise, there have been no
reports of how sustained CPAP treatment might affect mood and
sleep in this patient population although most studies in non-de-
mented subjects have found that long-term CPAP use improved
general sense of well-being and reduced daytime sleepiness.30-35
Despite our positive findings, there are several limitations
that warrant discussion. First, it is impossible to make causal in-
ferences given the small sample size and lack of random assign-
ment to group (continued use versus discontinuation of CPAP).
In addition, selection bias should be considered as the CPAP+
and CPAP− groups may have had intrinsic unmeasured differ-
ences which resulted in their choice to continue or discontinue
CPAP. As follow-up evaluations were not a part of the parent
study design, there are no objective measures of CPAP compli-
ance; nevertheless, the CPAP+ group did continue to have AHI
Figure 1—Changes in the CPAP+ and CPAP− groups from the end
of the RCT to follow-up on the depression, daytime sleepiness and
sleep quality scales. CSD: Although neither group had depressive
symptoms at the end of the RCT, at follow-up, the CPAP+ group
continued having no depressive symptoms (CSD < 6) (effect size
= 1.3) while the CPAP− group showed an increase in CSD scores
suggesting deterioration in mood (CSD > 6); ESS: Neither group
had evidence of daytime somnolence at the end of the RCT; how-
ever, at follow-up, the CPAP+ group’s ESS result was unchanged
while the CPAP− group’s ESS score was consistent with clinically
significant daytime sleepiness (effect size = 0.8); PSQI: CPAP+
group showed a significant clinical and statistical improvement
in PSQI while the CPAP− group showed a clinical and statistical
deterioration (effect size = 1.8, p < 0.05 by both Student’s t-test
and Mann-Whitney test).
Table 1—Neuropsychological Measures
*Higher HVLT score implies more recall; Higher WAIS speed implies completing the task faster; Lower Trails A score implies completing the
task faster; Lower Trails B score implies completing the task faster; Higher WCST score implies completing more of the task; Higher Stroop
score implies being able to read more color/words; Higher FAS letter score implies the ability to think of more words; Higher FAS animal
score implies the ability to think of more words; Higher Digit cancellation score implies completing more of the task. **p value = 0.06 from
the Student’s t-test and Mann-Whitney test.
Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009
8. Sullivan CE, Berthon-Jones M, Issa FG, Eves L. Reversal of ob-
structive sleep apnoea by continuous positive airway pressure ap-
plied through the nares. Lancet 1981;4:862-5.
Ancoli-Israel S, Palmer BW, Cooke JR, et al. Effect of treating
sleep disordered breathing on cognitive functioning in patients
with Alzheimer’s disease: a randomized controlled trial. J Am
Geriatr Soc 2008;56:2076-2081.
10. Chong MS, Ayalon L, Marler M, et al. Continuous positive air-
way pressure reduces subjective daytime sleepiness in patients
with mild to moderate Alzheimer’s disease with sleep disordered
breathing. J Am Geriatr Soc 2006;54:777-81.
11. Ayalon L, Ancoli-Israel S, Stepnowsky C, et al. Adherence to
continuous positive airway pressure treatment in patients with
Alzheimer’s disease and obstructive sleep apnea. Am J Geriatr
12. Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A
practical method for grading the cognitive state of patients for the
clinician. J Psychiatr Res 1975;12:189-98.
13. Cooke JR, Liu L, Natarajan L, et al. The effect of sleep disordered
breathing on sleep stages in patients with Alzheimer’s disease.
Behav Sleep Med 2006;4:219-27.
14. Buysse DJ, Reynolds CRI, Monk TH, Hoch CC, Yeager AL,
Kupfer DJ. Quantification of subjective sleep quality in healthy
elderly men and women using the Pittsburgh Sleep Quality Index
(PSQI). Sleep 1991;14:331-8.
15. Johns MW. A new method for measuring daytime sleepiness: The
Epworth sleepiness scale. Sleep 1991;14:540-5.
16. Weaver TE, Laizner AM, Evans LK, et al. An instrument to mea-
sure functional status outcome for disorders of excessive sleepi-
ness. Sleep 1997;20:835-43.
17. Alexopoulos GS, Abrams RC, Young RC, Shamoian CA. Cornell
scale for depression in dementia. Biol Psychiatry 1988;23:271-84.
18. Cummings JL. The Neuropsychiatric Inventory: assessing psy-
chopathology in dementia patients. Neurology 1997;48:S10-16.
19. Mattis S. Mental status examination for organic mental syndrome
in the elderly patient. In: Bellak L, Katasu TB, eds. Geriatric psy-
chiatry: a handbook for psychiatrists and primary care physicians.
New York: Grune & Stratton, 1976:77-121.
20. Mohs RC, Knopman D, Petersen RC, et al. Development of cog-
nitive instruments for use in clinical trials of antidementia drugs:
additions to the Alzheimer’s Disease Assessment Scale that
broaden its scope. The Alzheimer’s Disease Cooperative Study.
Alzheimer Dis Assoc Disord 1997;11 Suppl 2:S13-S21.
21. Reitan RM, Wolfson D. The Halstead-Reitan neuropsychological
test battery: Theory and clinical interpretation. 2nd ed. Tucson:
Neuropsychology Press; 1998.
22. Wechsler D. Wechsler Adult Intelligence Scale–Third Edition
(WAIS-III). San Antonio, TX: The Psychological Corporation,
23. Benedict RH, Schretlen D, Groninger L, Brandt J. Hopkins Verbal
Learning Test– Revised: normative data and analysis of inter-form
and test-retest reliability. Clin Neuropsychol 1998;12:43-55.
24. Brandt J. The Hopkins Verbal Learning Test: Development of a
new memory test with six equivalent forms. Clinical Neuropsy-
25. Heaton RK, Chelune GJ, Talley JL, Kay GG, Curtiss G. Wiscon-
sin card sorting test manual: Revised and expanded. Odessa, FL:
Psychological Assessment Resources, Inc, 1993.
26. Heaton RK. The Wisconsin Card Sorting Test: 64 card research
edition. Odessa, Fl: Psychological Assessment Resources, Inc,
27. Golden CJ. Stroop color and word test: a manual for clinical and
experimental uses. Wood Dale, IL: Stoelting Co, 1978.
28. Gladsjo JA, Schuman CC, Evans JD, Peavy GM, Miller SW,
Heaton RK. Norms for letter and category fluency: demo-
levels < 5 suggesting that they did indeed continue to use their
CPAP. Finally, these subjects were matched by time of com-
pletion of the initial RCT, not by other potentially important
variables such as gender, body mass index, severity of OSA,
or baseline cognitive function. More rigorous matching was
not possible due to the available small sample size. Because of
these study limitations, the results should be interpreted with
caution and need to be confirmed.
These findings do however raise the interesting possibil-
ity that the sustained, long-term use of CPAP may result in a
slowing in the rate of cognitive deterioration and in improve-
ments in sleep and mood in patients with mild to moderate AD
and OSA. In this study, even with a very small sample size, we
found moderate-to-large effect sizes with statistically signifi-
cant improvements in sleep quality for those participants who
continued to use CPAP. Given the potential positive impact
that CPAP use may have on cognition as well as mood and
sleep measures in AD patients and their caregivers, these pos-
sibilities should be evaluated through prospective randomized
Susan Lawton, Feng He, M.A., Deborah Greenfield M.A.,
and Matthew Marler, Ph.D. for assistance with the project.
Supported by: NIA AG08415, NIH M01 RR00827, NIA P50
AG05131, Research Service of the Veterans Affairs San Diego
This was not an industry supported study. Dr. Ancoli-Israel
has consulted for and/or is on the advisory board of Ferring
Pharmaceuticals, GlaxoSmithKline, Orphagen Pharmaceuti-
cals, Pfizer, Respironics, Sanofi-Aventis, Sepracor, and Scher-
ing-Plough and has received research support from Sepracor
and Litebook, Inc. The other authors have indicated no financial
conflicts of interest.
1. Ancoli-Israel S, Klauber MR, Butters N, Parker L, Kripke DF.
Dementia in institutionalized elderly: relation to sleep apnea. J
Am Geriatr Soc 1991;39:258-63.
Ancoli-Israel S, Coy TV. Are breathing disturbances in elderly
equivalent to sleep apnea syndrome? Sleep 1994;17:77-83.
Bliwise DL. Review: Sleep in normal aging and dementia. Sleep
Redline S, Strauss ME, Adams N, et al. Neuropsychological func-
tion in mild sleep-disordered breathing. Sleep 1997;20:160-7.
Ancoli-Israel S. Epidemiology of sleep disorders. Clin Geriatr
Taylor W, Phillipson EA, Moldofsky H. Cognitive function and
sleep disorderd breathing in normal elderly and patients with
Alzheimer’s disease. In: Kuna ST, Suratt PM, Remmers JE,
eds. Sleep and respiration in aging adults. New York: Elsevier,
Hoch CC, Reynolds CFI. Cognitive function and sleep disor-
dered breathing in dementia: the Pittsburgh experience. In: Kuna
ST, Suratt PM, Remmers JE, eds. Sleep and respiration in aging
adults. New York: Elsevier, 1991:245-50.
JR Cooke, L Ayalon, BW Palmer et al
Journal of Clinical Sleep Medicine, Vol.5, No. 4, 2009 Download full-text
32. Engleman HM, Kingshott RN, Wraith PK, MacKay TW, Deary
IJ, Douglas NJ. Randomized placebo-controlled crossover trial of
continuous positive airway pressure for mild sleep apnea/hypo-
pnea syndrome. Am J Respir Crit Care Med 1999;159:461-7.
33. Sateia MJ. Neuropsychological impairment and quality of life in
obstructive sleep apnea. Clin Chest Med 2003;24:249-59.
34. Sanner BM, Klewer J, Trumm A, Randerath W, Kreuzer I, Zidek
W. Long-term treatment with continuous positive airway pressure
improves quality of life in obstructive sleep apnoea syndrome.
Eur Respir J 2000;16:118-22.
35. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of con-
tinuous positive airway pressure treatment on daytime function in
sleep apnoea/hypopnoea syndrome. Lancet 1994;343:572-5.
graphic corrections for age, education and ethnicity. Assessment
29. Spreen O, Strauss E. A compendium of neuropsychological tests:
Administration, norms and commentary. 2nd ed. New York: Ox-
ford University Press; 1998.
30. Derderian SS, Bridenbaugh RH, Rajagopal KR. Neuropsycho-
logic symptoms in obstructive sleep apnea improve after treat-
ment with nasal continuous positive airway pressure. Chest
31. Millman RP, Fogel BS, McNamara ME, Carlisle CC. Depres-
sion as a manifestation of obstructive sleep apnea: reversal with
nasal continuous positive airway pressure. J Clin Psychiatry