Hiroshi Kadotani, Tomiko Kadotani, Terry Young, Paul E. Peppard, Laurel Finn, Ian M. Colrain, Greer M. Murphy, Jr, Emmanuel Mignot. Association Between Apolipoprotein E ∊4 and Sleep-Disordered Breathing in Adults. JAMA. 2001;285(22):2888–2890. doi:10.1001/jama.285.22.2888
Author Affiliations: Center for Narcolepsy (Drs H. Kadotani, T. Kadotani, and Mignot), and Department of Psychiatry and Behavioral Sciences (Drs H. Kadotani, T. Kadotani, Murphy, and Mignot), Stanford University School of Medicine, Stanford, Calif; Department of Pediatrics, Kobe University School of Medicine, Kobe, Japan (Dr T. Kadotani); Department of Preventive Medicine, University of Wisconsin, Madison (Drs Young and Peppard, and Ms Finn); Stanford University Sleep Disorders Clinic, Palo Alto, Calif (Dr Colrain); and Veterans Affairs Sierra-Pacific Mental Illness Research, Education, and Clinical Center, Palo Alto, Calif (Dr Murphy).
Context Apolipoprotein E ∊4
(ApoE ∊4) is a well-known risk factor for Alzheimer disease and
cardiovascular disease. Sleep-disordered breathing occurs in Alzheimer disease
patients and increases risks for cardiovascular disease. Complex interactions
among sleep, brain pathology, and cardiovascular disease may occur in ApoE
Objective To study whether genetic variation at the level of ApoE is associated with sleep-disordered breathing or sleep abnormalities
in the general population.
Design, Setting, and Participants Ongoing longitudinal cohort study of sleep disorders at a US university
beginning in 1989, providing a population-based probability sample of 791
middle-aged adults (mean [SD] age, 49  years; range, 32-68 years).
Main Outcome Measure Nocturnal polysomnography to evaluate apnea-hypopnea index.
Results The probability of moderate-to-severe sleep-disordered breathing (apnea-hypopnea
index ≥15%) was significantly higher in participants with
∊4, independent of age, sex, body mass index, and ethnicity (12.0% vs
7.0%; P = .003). Mean (SEM) apnea-hypopnea index
was also significantly higher in participants with ApoE ∊4 (6.5 [0.6] vs 4.8 [0.3]; P = .01). These
effects increased with the number of ApoE ∊4
Conclusions A significant portion of sleep-disordered breathing is associated with ApoE ∊4 in the general population.
Sleep-disordered breathing (SDB) is prevalent but largely undiagnosed
in adults.1 Persons with SDB are at increased
risk for hypertension2,3 and have
increased cardiovascular disease (CVD) morbidity and mortality.4
Characteristics of SDB, including changes in sleep architecture and electroencephalogram
(EEG) slowing, are also present in persons with Alzheimer disease (AD).5,6 Apolipoprotein E (ApoE), a protein
involved in lipid metabolism, has 3 major allelic variants:
∊4. While a protective effect for AD may be conferred by the ApoE ∊2 allele, risks for CVD and AD are increased by the ApoE
In this study, we assessed the contribution of ApoE genetic variation to SDB,
sleep architecture, and other sleep parameters.
Data were obtained from participants in an ongoing longitudinal cohort
study of sleep disorders that began in 1989.3
The cohort was constructed with a 2-stage probability sampling procedure on
a random sample of employed men and women to maximize variability in SDB.1,9 Every 4 years, participants underwent
overnight polysomnography, blood sampling, and other tests. Informed consent
was obtained in writing, using forms approved by the University of Wisconsin
institutional review committee.
Studies involving participants who had fewer than 5 hours of polysomnographically
documented sleep or who used psychotropic drugs were excluded (n = 558 studies).
A total of 1344 overnight studies in 791 participants (up to 3 studies per
participant) were included.
Sleep architecture and episodes of apnea and hypopnea were determined
with standard in-laboratory polysomnography that included electroencephalography
(EEG), electro-oculography, electromyelography, oximetry to detect arterial
oxyhemoglobin saturation, thermistry and nasal pressure to detect airflow,
and respiratory inductance plethysmography to record rib cage and abdominal
excursions of breathing. Each 30-second epoch of the polysomnographic records
was visually inspected and scored by trained technicians for sleep stage,
apnea (≥10 seconds with no breathing), and hypopnea (a discernible reduction
in the amplitude of respiratory inductance plethysmography associated with
a ≥4% reduction in oxyhemoglobin saturation). The average number of apneas
and hypopneas per hour of sleep (apnea-hypopnea index [AHI])3
was used as the summary measure of SDB. An EEG-slowing index (ratio of slow
[delta and theta] to fast [alpha and beta] frequencies in eyes-closed, awake
C3/A2 EEG) was calculated using fast Fourier spectral analysis6
on a subset of sleep studies with an adequate duration of quiet awake measurement
(n = 381). Apolipoprotein E genotype was determined using the polymerase chain
reaction–restriction fragment length polymorphism method.10
Serum cholesterol, triglyceride, and glucose levels were also measured.
Statistical techniques for data with repeated measures were used for
our data of up to 3 studies per participant on factors with intraparticipant
variation, including sleep architecture, AHI, and biochemical markers (SAS
8.0 software, SAS Institute, Cary, NC). Statistical analyses included repeated
measures analysis of covariance regression for continuous outcomes (SAS PROC
MIXED) and logistic regression for binary outcomes using the generalized estimating
equations approach for repeated measures (SAS PROC GENMOD). Regression analyses
were adjusted for potential confounding variables and for correlated observations
within participants for multiple sleep studies. A binary outcome (AHI ≥15)
was used to indicate clinically significant sleep apnea.
Allele frequencies for ApoE
∊4 were 0.07, 0.78, and 0.15, respectively. Low-density lipoprotein (LDL)
and triglycerides were increased while high-density lipoprotein (HDL) was
∊4-negative participants (Table 1). Mean (SEM) total cholesterol and LDL were both decreased in
participants (total cholesterol: 194  mg/dL vs 206  mg/dL, P<.001; LDL: 117  mg/dL vs 131  mg/dL, P<.001) (to convert mg/dL to mmol/L, multiply values by 0.0259).
None of the other parameters differed between
∊2-negative participants (data not shown).
A significant association between ∊4 and SDB
was found. The prevalence of elevated (≥15) AHI and mean AHI were both
significantly increased in ∊4-positive participants
independent of age, sex, BMI, and ethnicity (Table 1 and Table 2).
This association was present in both sexes (data not shown) and more pronounced
in the 14 ApoE ∊4 homozygous
participants of the cohort (24 sleep studies) (Table 2). Sleep architecture, EEG slowing (untransformed and log
transformed) did not differ with ApoE ∊4 status (Table 1).
Our results indicate that ApoE ∊4 is associated with sleep apnea. We also found that ApoE ∊2 is associated with
lower levels of total and LDL cholesterol while ∊4 is associated with higher levels of LDL and triglycerides, as previously
reported.7 Sleep-disturbed breathing has been
reported to cluster in families11,12
and ∊4 might be 1 of the multiple genetic factors
involved in susceptibility to this syndrome. Of note, SDB prevalence increases
with aging,1,13 and our sample
is that of middle-aged adults. We found a substantial effect of ∊4 on SDB: there was a 2-fold increase in the odds of SDB
(Table 2) in ∊4-positive vs ∊4-negative participants.
Considering the prevalence of the ∊4 polymorphism
(15%), up to 8% of AHI (15) in the general population might be caused by the
effects of ∊4.
Only 1 study has examined the effect of ∊4
on SDB.14 In that study, participants with
sleep apnea were more likely to be ∊4 homozygotes
than were controls, but the difference was not statistically significant.
The controls were mostly middle-aged men who had not been studied for SDB.
Up to 9% of middle-aged men in the general population have an AHI of 15 or
more,1 so it is likely that the control group
contained men with SDB, which would underestimate the association of ∊4 and SDB. Our study is unique because every participant
has undergone nocturnal polysomnography, with most having been studied several
Another report suggests significant interactions among sleep, AD, and
the ∊4 genotype, with a higher risk of AD morbidity
present in ∊4-positive participants who napped
for more than 60 min/d.15 Sleep-disordered
breathing causes daytime sleepiness and prolonged napping. Thus, increased
SDB in ∊4-positive participants might be responsible,
at least partially, for this interaction.
Our finding is a simple statistical association that does not indicate
a causal relationship between ApoE ∊4 and sleep
apnea. A complex syndrome, SDB involves the central control of breathing and
peripheral predisposing factors, leading to anatomical narrowing and collapse
of the upper airway during sleep. Thus, SDB frequently occurs after such brain
injuries as head trauma16 and stroke,17 demonstrating the importance of central factors.
On the other hand, ∊4 may increase the density
of β-amyloid deposits and neurofibrillary tangles in nondemented individuals.7,8 Increased pathology in sleep/respiratory
centers might contribute to centrally mediated SDB in ∊4-positive participants. Additional studies are needed to extend these
The increased SDB prevalence in ∊4-positive
participants may have clinical consequences. The established cardiovascular
impact of SDB and the deleterious effect of ∊4
on lipid metabolism may have synergistic effects. Sleep-disordered breathing
and ∊4 could also interact centrally to impair
cognition. Not only may ∊4 predispose to neurodegenerative
changes, but also SDB induces sleepiness and may damage the brain irreversibly
through long-term hypoxemia.18,19
Further studies will be needed to confirm and extend these findings.