Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: ...

Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: Mechanism for cognitive dysfunction and development of dementia

Sleep apnea is prevalent among patients with trau-
matic brain injuries (TBIs), and initial studies suggest it is
associated with cognitive impairments in these patients. Recent
studies found that the apolipoprotein epsilon 4 (APOE epsilon 4)
allele increases the risk for sleep disordered breathing, particu-
larly sleep apnea. The APOE epsilon 4 allele is associated with
cognitive decline and the development of dementia in the general
population as well as in patients with TBI. These findings raise
the question of whether patients with TBI who are APOE epsi-
lon 4 allele carriers are more vulnerable to the negative effects
of sleep apnea on their cognitive functioning. While few treat-
ments are available for cognitive impairment, highly effective
treatments are available for sleep apnea. Here we review these
different lines of evidence, making a case that the interactive
effects of sleep apnea and the APOE epsilon 4 allele represent
an important mechanism by which patients with TBI may
develop a range of cognitive and neurobehavioral impairments.
Increased understanding of the relationships among sleep
apnea, the APOE epsilon 4 allele, and cognition could improve
our ability to ameliorate one significant source of cognitive
impairment and risk for dementia associated with TBI.

Key words: Alzheimer disease, apolipoprotein epsilon 4, cog-
nition, daytime sleepiness, dementia, mild cognitive impair-
ment, obstructive sleep apnea, sleep apnea, sleep disordered
breathing, traumatic brain injury.

Abbreviations: AD = Alzheimer disease, APOE ε4 = apolipo-
protein epsilon 4, BiPAP = bilevel positive airway pressure, CI =
confidence interval, CPAP = continuous positive airway pres-
sure, CSA = central sleep apnea, MCI = mild cognitive impair-
ment, MinSaO2 = minimum level of arterial oxygen saturation,
NFT = neurofibrillary tangle, OR = odds ratio, OSA = obstruc-
tive sleep apnea, RDI = Respiratory Disturbance Index, SDB =
sleep disordered breathing, SNP = single nucleotide polymor-
phism, TBI = traumatic brain injury, VA = Department of Vet-
erans Affairs.


O'Hara R, Luzon A, Hubbard J, Zeitzer JM. Sleep apnea, apolipoprotein epsilon 4 allele, and TBI: Mechanism for cognitive dysfunction and development of dementia. JRRD 2009; 46(6):837-850.

INTRODUCTION

In recent years, there has been an increased focus on
the prevalence and impact of sleep apnea in traumatic
brain injury (TBI). Sleep apnea is well documented to
negatively affect neurocognitive and neuropsychiatric
functioning, including memory, attention, mood, and
anxiety. Sleep apnea has recently been implicated in cog-
nitive decline and risk for developing Alzheimer disease
(AD). TBI has long been identified as a risk factor for the
development of dementia, with some studies suggesting
the risk is greater among those with the vulnerability fac-
tor for AD, apolipoprotein epsilon 4 (APOE ε4) allele.
Herein we review the literature to date on sleep apnea in
TBI and outline the evidence to suggest that these factors
in combination with the presence of the APOE ε4 may
contribute significantly to cognitive dysfunction and the
development of dementia in these patients. Because the
majority of sleep apnea patients are male and TBI is com-
mon among veterans because of combat and other fac-
tors, this work has significant importance for the
Department of Veterans Affairs (VA).


PREVALENCE OF SLEEP DISORDERED
BREATHING IN TBI

Recent evidence suggests an increased incidence of
sleep disordered breathing (SDB) in TBI patients, with
prevalence ranging from 25 [1] to 35 percent [2] compared
with 4 to 9 percent in the general world population [3].
A recent investigation of sleep disorders in patients with
TBI suggests as many as 50 to 70 percent of patients with
TBI may suffer from some form of SDB [4]. These
authors concluded that treatable sleep disorders, such as
SDB, may be largely undiagnosed and untreated in the
patient population with TBI. One initial investigation
also suggests that SDB is associated with cognitive
impairment in patients with TBI [3].

One of the most common forms of SDB is sleep
apnea, of which obstructive sleep apnea (OSA) is by far
the most prevalent. OSA is defined by frequent episodes
of obstructed breathing during sleep. Specifically, it is
characterized by sleep-related decreases (hypopneas) or
pauses (apneas) in respiration with a characteristic asso-
ciation of snoring and excessive daytime sleepiness [5–
6]. The diagnosis of OSA is confirmed when the patient
presents with excessive daytime sleepiness and a Respi-
ratory Disturbance Index (RDI) of >5 ((apneas + hypop-
neas) ÷ total sleep time in hours) [7]. However, in
general, referral for treatment is not considered for indi-
viduals exhibiting an RDI <10 but is routinely considered
when an RDI is particularly elevated, even in the absence
of daytime sleepiness. An obstructive apnea is defined as
interruption of oronasal airflow of at least 10 seconds,
corresponding to a complete obstruction of the upper air-
ways (despite continuous chest and abdominal move-
ments) associated with a decrease in oxygen saturation
and/or arousals from sleep. An obstructive hypopnea is
defined as at least 10 seconds of partial obstruction of the
upper airways, resulting in an at least 50 percent decrease
in oronasal airflow. These abnormal respiratory events
are generally accompanied by heart rate variability and
arousals from sleep, with frequent arousals being the
most important factor in resultant excessive daytime
sleepiness.

The prevalence of OSA is higher in men than in
women [8]. OSA is found in all age groups, but despite a
lifetime prevalence of between 4 and 9 percent in the gen-
eral population, its prevalence increases with age [9]. In
subjects between the ages of 30 and 65 years, 24 percent of
men and 9 percent of women had OSA. Among subjects
over 55 years, 30 to 60 percent have an RDI >5 [10]. In a
population of community-dwelling older adults, 70 percent
of men and 56 percent of women between the ages of 65
and 99 years have evidence of OSA with a criterion of
RDI >10 [11].

Effective treatments are available for the alleviation of
OSA. Treatment for mild cases includes weight loss, dental
devices (which advance the tongue or mandible to increase
posterior airway space), or upper airway surgery [12].
Additionally, positional therapies have been employed with
success, with patients urged to sleep on their front or sides
rather than their backs. The gold standard treatment, how-
ever, for moderate to severe cases of OSA is continuous or
bilevel positive airway pressure (CPAP/BiPAP) [13]. Other
upper airway surgical procedures can be used for particular
cases with craniofacial abnormalities [14].

Sleep apnea can be readily characterized with objective
measurements of breathing and electroencephalography
during an overnight sleep episode. Yet many individuals
who, on objective measures, have severely disturbed sleep
due to sleep apnea often fail to realize that their sleep is dis-
turbed; more often they describe impaired daytime alert-
ness. This lack of awareness may be exacerbated in patients
with severe TBI as these individuals may be unaware of
their sleep problems because of cognitive or neurological
deficits from their injury or a preoccupation with more
immediate medical aspects of their injury. In general, those
with severe TBI report fewer posttrauma symptoms than
those with lesser injuries [15]. Those with mild trauma may
be more aware of their sleep issues because of their capac-
ity to be more acutely aware and sensitive to post-TBI neu-
rological and neuropsychiatric changes. Indeed, disrupted
sleep is a common complaint among patients with TBI
[16]. Some of the observed sleep disruption in TBI may be
due to sleep apnea.


SLEEP APNEA, TBI, COGNITIVE FUNCTIONING,
AND DEMENTIA

Sleep apnea is well documented as being associated
with cognitive impairment. Impairments in attention
memory, psychomotor function, and executive function
have all been associated with sleep apnea [17–21]. One
of the most consistent findings is that sleep apnea nega-
tively affects delayed recall ability [22].

In a recent investigation of the effect of OSA on the
cognitive functioning of patients with TBI, Wilde et al.
found not only an increased incidence of OSA in patients
with TBI but also a resultant decrease in the domains of
delayed recall, attention, vigilance, and retention of both
verbal and visual information in patients with both TBI
and OSA [3]. Thirty-five patients with TBI were admin-
istered a comprehensive neuropsychological battery and
assessed for OSA based on standard criteria with noctur-
nal polysomnography. Nineteen patients with TBI had
both OSA and TBI and were compared with sixteen
patients who had a TBI and no presence of OSA. Both
groups were comparable with respect to age, education,
severity of injury, time postinjury, and rating on the Glas-
gow Coma Scale. While the group with OSA and TBI
had more attentional lapses, both groups performed com-
parably on measures of motor, visual construction, and
attentional performance. However, patients with TBI
with OSA performed significantly worse than the non-
sleep-disordered patients with TBI on measures of both
verbal and visual delayed recall.

Impaired delayed recall is a hallmark of typical and
pathological cognitive aging and is a key feature of AD.
TBI itself is a noted risk factor for dementia. Dementia is
an age-related progressive disorder characterized by loss
of function in multiple cognitive domains that is severe
enough to cause impairment in social and occupational
functioning.

AD is the most common form of dementia, account-
ing for between 50 and 70 percent of all cases. It is a neu-
rodegenerative disorder, characterized neuropathologically
by widespread neuronal loss, presence of neurofibrillary
tangles (NFTs), and deposits of amyloid beta in cerebral
blood vessels and neuritic plaques. The medial-temporal
lobes, hippocampus, and association cortex are preferen-
tially affected, leading to a marked decline in cognitive
functioning that is the hallmark feature of AD [23].
While individuals with dementia or AD experience cog-
nitive impairment, not all cognitive impairment repre-
sents a neurodegenerative disorder. One of the clearest
findings to emerge from the field of cognitive aging is
that performance on measures of memory and attention
worsens with advancing age, which is regarded as part of
the normal aging process. However, many older adults
find these changes debilitating on a daily basis, interfer-
ing with activities ranging from medication compliance
to productivity in the workplace. Recognition of age-
associated cognitive and memory decline that appeared
to go beyond that typically associated with normal aging
led to the classification of such problems as cognitive
impairment or mild cognitive impairment (MCI), the
presence of which can significantly increase the likeli-
hood of developing AD or dementia. Indeed, the types of
cognitive and behavioral deficits exhibited appear to be
on a continuum of severity from those that hallmark AD
and dementia to MCI.


TBI AND RISK FOR DEMENTIA

The suggestion that TBI contributes to the develop-
ment of AD and dementia has a long past. As early as
1976, Khaime reported on three cases of AD that devel-
oped after brain injury [24]. Since then, numerous ani-
mal, experimental, and epidemiological studies have
supported an association between TBI and dementia.

Animal studies suggest that TBI contributes to the
development of core AD pathological features, including
increased oxidative stress [25] and increased levels of
amyloid beta [26–27]. Human postmortem studies have
observed both amyloid beta deposition and tau pathology
in patients with TBI [28–29]. Ikonomovic et al. con-
ducted an immunohistochemical study of AD-related
changes in temporal cortex resected from 18 patients
with TBI (aged 18–64 years) treated surgically for severe
TBI [30]. Diffuse cortical amyloid beta deposits were
observed in one-third of subjects (aged 35–62 years)
as early as 2 hours after injury, with only one individual
(35 years of age) exhibiting “mature” dense-cored plaques.
Tau-positive, NFT-like changes were detected in only two
subjects, both of whom were more advanced in age and
had no evidence of amyloid beta deposits. No sex differ-
ences were found among the three diagnostic groups. The
authors suggested that amyloid beta plaques and early
evidence of neuronal degenerative changes may develop
rapidly after TBI, while fully developed NFTs may result
from more chronic disease- or injury-related processes.

The great majority of epidemiological investigations
observe an association between TBI and the development
of dementia [31–38], although some negative findings
exist [39–41]. In one of the largest studies of veterans
with TBI, Plassman et al. examined the association
between early adult head injury, as documented by mili-
tary hospital records, and dementia in late life [42]. Both
moderate and severe head injury were associated with
increased risk of AD. The results for mild head injury
were inconclusive, but overall the findings suggested that
moderate and severe head injuries in young men were
associated with increased risk of AD and other dementias
in later life.

Fleminger et al. [43] undertook a replication and
extension of the meta-analysis of Mortimer et al. [44] by
conducting a comprehensive and systematic search of
electronic databases through August 2001. Fifteen case-
control studies were identified that met the inclusion cri-
teria, of which seven postdated Mortimer et al.’s study.
Analysis of all 15 case-control studies was significant
(odds ratio [OR] 1.58, 95% confidence interval [CI]
1.21–2.06), indicating a history of head injury in those
with AD. Also, the authors replicated the finding of Mor-
timer et al., who found that head injury is a risk factor for
AD only in males (males: OR 2.29, 95% CI 1.47–2.06;
females: OR 0.91, 95% CI 0.56–1.47) [43].

One proposed explanation for the sex difference in
the risk of AD following head injury is the role of the
female hormones, such as estrogen and progesterone.
Animal models of stroke and TBI suggest that these hor-
mones may confer a neuroprotective effect. Bramlett and
Dietrich, for example, employed an animal model of TBI
and found contusion volume was significantly smaller in
adult female rats than in male and ovariectomized female
rats [45]. Estrogen has been implicated as a potential pro-
tective factor in the development of AD, although find-
ings are mixed [46]. Whether females may be protected
from AD following head injury because of the protective
effects of female hormones remains to be more systemati-
cally investigated.


TBI AND APOE ε4 ALLELE: INCREASED
VULNERABILITY FOR DEMENTIA

Recent evidence points to a potential overlapping
pathophysiological mechanism underlying the negative
effect of both sleep apnea and TBI on cognitive function-
ing. Several investigators suggest that the APOE ε4 allele
is a brain vulnerability marker and that APOE ε4 allele
carriers have a limited capacity to respond to physiologi-
cal challenges and, hence, are more prone to cognitive
deficits and poor recovery after insults to the nervous
system [44,47–48]. The APOE ε4 allele is a noted
genetic risk factor for the development of AD, and as
many as 30 percent of individuals with MCI and cogni-
tive impairment carry an APOE ε4 allele [23]. APOE is a
plasma protein that is involved in the transport of choles-
terol and other lipids. The APOE protein is expressed by
a gene on chromosome 19 with three allelic variants (ε2,
ε3, ε4), resulting in six possible genotypes. It is present in
senile plaques, NFTs, and cerebrovascular amyloid, the
major neuropathological changes in AD, and is impli-
cated in the growth and regeneration of nerves during
development and/or following injury. The APOE ε4 allele
thus appears to interact with other factors to increase
vulnerability to cognitive and neurological problems,
including dementia [44,47–50].

Presence of the APOE ε4 allele has been documented
to increase vulnerability to negative neurocognitive and
functional outcomes in TBI. Hartman et al. found that
APOE ε4 allele influenced amyloid deposition but not
cell loss after TBI in a mouse model of AD [27]. Tang et
al. observed a tenfold increase in the risk of AD among
those who were both APOE ε4 carriers and had a history
of TBI [51]. Head injury in non-APOE ε4 carriers did not
increase risk. Luukinen et al. found fall-related TBI to
predict earlier onset of dementia, particularly in APOE ε4
carriers [52], and Friedman et al. found APOE ε4 carriers
with TBI had significantly poorer functional outcome
[53]. However, there are also many mixed findings with
respect to the relationship between APOE genotype and
TBI. Millar et al. found that although they observed late
cognitive decline to occur after head injury, there was no
clear relation to APOE genotype [54]. Replicating the
finding of Guo et al., who found that TBI increased the
risk for AD in non-APOE ε4 carriers only [55], Jellinger
et al. conducted the first retrospective autopsy study of
TBI, APOE ε4 allele frequency, and AD, in which they
also found that severe TBI was a risk factor for the devel-
opment of AD, most particularly in non-APOE ε4 carri-
ers [56–57]. But we should note that the sample size was
very small in the work of Jellinger et al. and many of the
negative studies generally focused upon the most severe
cases of TBI. Mauri et al. obtained TBI history in 337
subjects with probable AD and 63 subjects with MCI
[58]. A high frequency of the APOE ε4 allele was
detected in those with cognitive impairment (40.5% in
the AD and 11% in the MCI subgroups). O’Meara et al.
suggested that the APOE ε4 allele and TBI may represent
independent risk factors for dementia [59].

In one of the most comprehensive investigations of this
issue, Sundström et al. examined the relationship of mild
levels of TBI and APOE ε4 to risk for dementia using data
from the Betula prospective population-based study of
aging, memory, and health [60]. These data included
information on 543 subjects, aged 40 to 85 years, who
were free of dementia at baseline and who were followed
up within a 5-year interval. Dementia was classified using
Diagnostic and Statistical Manual of Mental Disorders-IV
criteria, and information on previous head injury was
obtained through screening of the participants’ answers to
health questionnaires at both baseline and at follow-up. The
authors found that non-APOE ε4 carriers with head injury
did not have an increased risk of dementia. However,
APOE ε4 carriers had an increased risk for dementia (OR =
2.3), and those APOE ε4 carriers who also had mild head
injury had a statistically significant, higher risk of
developing dementia (OR = 5.2). Further, Isoniemi et al.
examined the association of APOE genotype with long-
term outcome in 61 patients with TBI [61]. The long-term
outcome was evaluated with repeated neuropsychological
testing and by applying various measures of everyday func-
tioning and quality of life. After three decades, patients
with TBI who were APOE ε4 carriers showed a 63 percent
decline in general cognitive level as measured by Mental
Deterioration Battery Score compared with a 30 percent
decline in patients who were carriers of the APOE ε3 allele
and a 5 percent improvement in patients who were carriers
of the APOE ε2 allele.

Overall, these findings suggest a significant additive
negative effect of head trauma and presence of the APOE
ε4 allele on risk for dementia, such that the APOE ε4
allele and TBI conspire to confer a greater risk than either
the APOE ε4 allele or TBI alone. However, this risk may
increase according to the severity of the TBI and amount
of time elapsed since the TBI occurred.


SLEEP APNEA, TBI, AND APOE ε4 ALLELE

Presence of the APOE ε4 allele has also been found
to confer up to a twofold increased risk for OSA [62–63].
In a population-based probability sample of 791 middle-
aged adults (mean ± standard deviation age = 49 ±
8 years, range = 32–68 years), the probability of mod-
erate-to-severe SDB was significantly higher in partic-
ipants with the APOE ε4 allele, independent of age, sex,
body mass index, and race/ethnicity [63]. Although nega-
tive findings exist, most recently, Gottlieb et al. examined
1,775 subjects and confirmed an age-dependent associa-
tion between the allele and sleep apnea [62].

Further, O’Hara et al. found that sleep apnea inter-
acted with the APOE ε4 allele to negatively affect mem-
ory and suggested that APOE ε4 carriers with sleep
apnea may be at increased risk for developing dementia
[64]. This finding has recently been independently repli-
cated by two groups: Gozal et al. found that children with
OSA and poor cognitive performance were much more
likely to be APOE ε4 carriers [65], and similarly, Con-
sentino et al. found that APOE ε4 carriers who had pres-
ence of OSA had lower performance on a working
memory task than those without apnea [66].

One recent investigation concentrated on several
known single nucleotide polymorphisms (SNPs) within
the APOE gene and its regulatory region in order to find
associations with OSA status among children. They
found that SNPs rs157580, rs405509, rs769455, and
rs7412 all showed associations with OSA status, with age
and body mass index as covariates. They concluded that
polymorphisms in more than one locus in the APOE gene
and its regulatory region are associated with OSA in chil-
dren [67]. This finding lends itself to the conclusion that
the interaction between TBI, OSA, and APOE genotype
may be more complex than originally thought.

Sleep apnea-related cognitive impairment in TBI
may reflect the hypoxia that accompanies sleep apnea
events, with some additional impairment resulting from
sleep fragmentation and daytime sleepiness [68].
Hypoxia is a defining feature of sleep apnea. Investiga-
tors have long suggested a model in which the neuronal
injury resulting from hypoxia results in sleep apnea-
associated cognitive impairment [68]. Hypoxic damage
resulting from a broad range of disorders (e.g., brain
injury, stroke, cardiac arrest) is well documented to nega-
tively affect function and cognition, although the litera-
ture on the relationship between sleep apnea-related
measures of hypoxia, such as minimum or average level
of oxygen desaturation, and cognitive function is quite
limited and the findings mixed [50,69–71]. In our own
clinical investigation, we found that although average
minimum level of arterial oxygen saturation (MinSaO2)
displayed a nonsignificant tendency to negatively interact
with the APOE ε4 allele to affect memory, the actual
number of respiratory events was most strongly associ-
ated with impaired cognition [50]. Although most studies
of this issue employ a single or average measure of oxy-
gen desaturation, interaction of duration, frequency, and
level of hypoxia, rather than MinSaO2 alone, may exert
the greatest clinical impact.

An alternate explanation is that apnea/hypopnea-
associated sleep fragmentation, rather than hypoxia per
se, negatively affects cognition. Individuals with neu-
ronal loss due to a TBI may be particularly vulnerable to
the hypoxic events that accompany sleep apnea, as well
as to the behavioral outcomes such as cognitive impair-
ment and depression that have been consistently associ-
ated with the presence of sleep apnea [57,72]. A recent
investigation by Chang et al. found that brain tissue
hypoxia is common among patients with TBI; however,
no measurement of apnea was included in this finding
[73]. Further studies are needed to determine the hypoxic
effect of sleep apnea in patients with TBI.

Animal studies suggest that the APOE ε4 allele
increases neuronal vulnerability to oxidative stress [74].
The suggestion that APOE ε4 exacerbates sleep apnea-
associated cognitive impairment by reducing the brain’s
response to the hypoxic events experienced during apnea
is consistent with observations that hypoxia and APOE
ε4 status impact the hippocampus. Hypoxia has negative
effects on neuronal integrity in the hippocampus [75–76].
These same hippocampal regions, which subserve
delayed recall, also appear vulnerable to deleterious
effects of the APOE ε4 allele [77–79]. Furthermore, our
preliminary data found a negative association between
even mild levels of sleep apnea and impaired delayed
recall only in those with the APOE ε4 allele. Further, the
common link between TBI and sleep apnea may be the
resultant hypoxic effects exerted on brain tissue by both
of these conditions, with presence of the APOE e4 allele
further mitigating against an effective neuronal recovery
response to the hypoxia.

Increased understanding of the relationships among
sleep apnea, APOE genotype, and hypoxia may provide
significant insight into the molecular mechanisms that
initiate critical pathological cascades in TBI. Further, the
effective treatments available for sleep apnea may go a
long way to improving the prognosis for patients with
TBI not only in terms of the pathophysiology associated
with the disorder but also in terms of improving the nega-
tive comorbid cognitive and psychiatric symptoms that
are so prevalent in TBI.


Treatment of Sleep Apnea in TBI

Sleep hygiene provides subjects with basic education
about daily behaviors, environmental conditions, and
other sleep-related factors that have the potential to inter-
fere with or support good sleep [80–81]. With respect to
sleep apnea, treatment studies indicate that CPAP/BiPAP
can be very effective in reducing not only sleep apnea
events but also the associated cognitive and affective
sequelae [64,72], although compliance can be difficult
for all patients. To date, no systematic studies have been
conducted on CPAP/BiPAP use in patients with TBI.
Given the effectiveness of this treatment approach, it may
be particularly valuable for alleviating a range of behav-
ioral and psychiatric symptoms in patients with TBI with
comorbid sleep apnea.


Sleep Apnea in TBI: Vulnerability Factor or
Mechanism for Impairment

Patients who present with OSA may actually be at
greater risk for TBI. OSA is well documented to cause
sleepiness, which increases the likelihood of having an
accident while driving [82]. Motor vehicle accidents may
result in TBI or other bodily damage. Sleepiness is a fac-
tor in 42 to 54 percent of motor vehicle collisions [2].
Evidence exists that the presence of OSA is associated
with increased risk for traffic accidents [83–84]. While
there may be some dual causality of TBI and OSA, the
direction of the relationship is still not clearly defined. In
the United States, 80,000 people become permanently
disabled from TBI as a result of motor vehicle crashes,
falls, acts of violence, and sports incidents each year [85].

Alternatively, sleep apnea in TBI may occur second-
ary to the brain injury itself. In contrast to OSA, central
sleep apnea (CSA) is defined as a lack of airflow accom-
panied by a lack of respiratory effort, reflecting impair-
ments in brain areas controlling breathing. The important
difference is that while in OSA, there is periodic apnea
and asphyxia from upper airway obstruction or collapse
in the pharynx, there is continued respiratory effort. CSA,
then, may be indicative of more severe TBI or brain mal-
formation [86].

In a recent study, patients who showed progression into
white matter disease assessed by longitudinal magnetic
resonance imaging scans were significantly more likely
to have an increased number of central rather than
obstructive apneas. This result led the investigators to
conclude that there is a causal pathway in which CSA
contributes to the progression of white matter disease
[86]. However, there may be a dual causality, in that it
may be the presence of white matter disease that contrib-
utes to CSA, which then in turn exacerbates the already
present white matter disease.

Webster et al. found that, in a relatively small study,
10 of 28 patients with TBI had sleep apnea and that the
majority of these events were central apneas rather than
obstructive apneas [87]. Normally, sleep apnea events are
about 90 percent obstructive and only 10 percent central
in nature [88]. Although the rate of sleep apnea was sig-
nificantly higher than would be predicted of population
norms, there was no correlation between presence of sig-
nificant sleep apnea and severity of TBI.


Sleep Apnea in TBI: Relevance to Veterans

Several investigators have suggested that sleep apnea
is highly prevalent in veteran populations, likely reflect-
ing the fact that there is increased prevalence of sleep
apnea with age and that this disorder is far more common
among men [89–90]. However, in a recent investigation
of more than 4,060,504 health records of veterans,
Sharafkhaneh et al. found very similar prevalence rates of
sleep apnea, namely 2.91 percent, to general population
rates [91]. The authors raised the concern that this may
reflect the fact that sleep apnea may be underdiagnosed
in the veteran population. Indeed, Mustafa et al. used a
self-report questionnaire to identify chronic symptoms of
sleep disorders among patients in VA medical centers and
found that with a mean age of 62.5 years, 47.4 percent
met high-risk criteria for sleep apnea [92]. Further,
Sharafkhaneh et al. found that those veterans with sleep
apnea had far higher rates of psychiatric and medical
comorbidity, including posttraumatic stress disorder, anxi-
ety, and dementia, than those without this disorder [91].

Not only is sleep apnea more prevalent in men but
the negative relationship of TBI to risk for dementia also
seems to be exacerbated in men. Van Duijn et al. con-
ducted a population-based case-control study of the asso-
ciation between head trauma and AD [93]. They
compared 198 patients with clinically diagnosed early
onset AD and 198 age- and sex-matched population con-
trols. Following adjustment for sex, age, family history
of dementia, and education, the OR of a history of head
trauma (with loss of consciousness) was 1.6 (95% CI
0.8–3.4). However, the OR for men was 2.5 (95% CI 0.9–
7.0), compared with 0.9 (95% CI 0.3–2.8) for women.
Thus, male veterans may be at increased risk not only for
sleep apnea itself but also for negative neurological and
neuropsychiatric consequences of this disorder.


SUMMARY AND CONCLUSIONS

Increased understanding of the relationships between
sleep apnea, APOE ε4 allele, and cognition could lead to
improved therapeutic approaches to the cognitive impair-
ment associated with TBI, as well as increasing our
understanding of the pathophysiological mechanisms
underlying the negative consequences of TBI.

Recovery from a TBI is often lengthy and difficult,
and this recovery process may be hampered by the pres-
ence of a comorbid sleep disorder. Disruption of normal
sleep by sleep apnea can also exacerbate other neuropsy-
chiatric sequelae of TBI, potentially leading to long-term
consequences and a decrement in overall quality of life.
Sleep apnea is very prevalent in the veteran population
and can be treated with one of the well-established and
effective treatment approaches, such as CPAP/BiPAP,
positional therapies, surgery, or weight loss. More sys-
tematic research is necessary in order to provide a foun-
dation for an evidence-based medical approach to the
treatment of sleep in the context of TBI. If, as the litera-
ture suggests, the APOE ε4 allele is associated with an
increased risk for sleep apnea, then sleep apnea may be
responsible for, i.e., mediate, any negative relationship
between the APOE ε4 allele and cognitive impairment in
TBI (Figure 1). Alternatively, any negative relationship
between sleep apnea and cognitive function in TBI may
reflect the increased vulnerability of APOE ε4 carriers to
the neurological effects of sleep apnea, specifically
apnea-associated hypoxia (Figure 2). As such, the APOE
ε4 allele would moderate the relationship between sleep
apnea and cognition in TBI. In this case, treatments for
sleep apnea might target only APOE ε4 carriers. Of
course, it is important to note that if there is a negative
additive effect of hypoxia and APOE ε4 on the risk for
dementia among patients with TBI, sleep apnea is not the
only disorder that can result in hypoxia. Conditions such
as chronic obstructive pulmonary disorder, pulmonary
fibrosis, and asthma, for example, can all result in
hypoxia, such that presence of any of these disorders
might increase the risk for dementia and cognitive
decline in patients with TBI. Another viable possibility is
that apnea/hypopnea-associated sleep fragmentation, rather
than hypoxia per se, negatively affects neurological and
neuropsychological outcomes. Future studies are required
to investigate this possibility.


________
Figure 1. Mediator model: Proposed model for obstructive sleep apnea (OSA) mediating negative association of apolipoprotein epsilon 4 (APOE ε4) on cognitive function in traumatic brain injury (TBI) patients. In this model, a significant association is found between APOE ε4 allele and OSA and OSA is responsible for observed increase in cognitive impairment and dementia in those with APOE ε4 allele; those without APOE ε4 allele display decreased OSA and no increase in cognitive impairment and dementia.
________

________
Figure 2. Moderator model: Proposed model for apolipoprotein epsilon 4 (APOE ε4) moderating negative effect of obstructive sleep apnea (OSA) on cognitive function in traumatic brain injury (TBI) patients. In this model, no significant association is found between APOE ε4 allele and OSA and the negative relationship between higher OSA and cognitive impairment and dementia reflects increased vulnerability of APOE ε4 carriers to effects of OSA.
________



Larger longitudinal studies are required to clarify
these issues—whether the APOE ε4 allele increases vul-
nerability to the negative effect of SDB on cognition in
patients with TBI or whether the relationship between
APOE ε4 and cognition is in fact due to the higher preva-
lence of SDB in these patients. Further, such longitudinal
prospective studies, with full polysomnography, are
required to address whether the relationship between
sleep apnea and risk for dementia and cognitive decline
in patients with TBI is mediated by the sleep-apnea asso-
ciated hypoxia or sleep fragmentation or moderated by
characteristics of the TBI itself, such as severity and
duration since onset. Such relationships could also be
examined within the context of treatment trials of CPAP,
for example, for sleep apnea in veterans with TBI.

Overall, however, the evidence suggests that patients
with TBI have an increased prevalence of sleep apnea.
Considering the high carrier frequency of the APOE ε4
allele in the general population (25%), this polymorphism
may account for a very substantial portion of the attribut-
able risk for sleep apnea. Given that the APOE ε4 allele is
also associated with increased risk for cognitive impair-
ment and decline, sleep apnea and the APOE ε4 allele
may conspire to both exacerbate cognitive impairment
and accelerate the cognitive decline in patients with TBI.
The risk for sleep apnea is greater in men. Given that the
majority of veterans are men who are also at increased
risk for TBIs, any relationship between sleep apnea and
cognitive dysfunction in this patient group is of particular
relevance and importance for the VA. While there are few
effective therapeutic approaches for cognitive impair-
ment, effective treatments for sleep apnea are available,
including weight loss, dental devices, upper airway sur-
geries, and CPAP/BiPAP. Increased understanding of the
relationships among sleep apnea, APOE ε4, and cognition
could lead to improved therapeutic approaches to the cog-
nitive impairment associated with TBI, as well as increase
our understanding of the pathophysiological mechanisms
underlying the negative consequences of TBI.


ACKNOWLEDGMENTS

Author Contributions:
Study concept and design: R. O’Hara.
Acquisition of data: R. O’Hara, A. Luzon, J. Hubbard.
Analysis and interpretation of data: R. O’Hara, A. Luzon, J. Hubbard,
J. M. Zeitzer.
Drafting of manuscript: R. O’Hara, A. Luzon, J. Hubbard,
J. M. Zeitzer.
Critical revision of manuscript for important intellectual content:
R. O’Hara, A. Luzon, J. Hubbard, J. M. Zeitzer.
Statistical analysis: R. O’Hara.
Obtained funding: R. O’Hara.
Administrative, technical, or material support: R. O’Hara, A. Luzon,
J. Hubbard.
Study supervision: R. O’Hara.

Financial Disclosures: The authors have declared that no competing
interests exist.

Funding/Support: This work was supported in part by the VA Sierra-
Pacific Mental Illness Research, Education, and Clinical Center
(MIRECC); the Stanford/VA Alzheimer’s Research Center; the
National Institutes of Health (grants MH 070886, AG 18784, and AG
17824); and the State of California Department of Health Services
(grant 06-55310).


REFERENCES

1. Castriotta RJ, Wilde MC, Lai JM, Atanasov S, Masel BE,
Kuna ST. Prevalence and consequences of sleep disorders in
traumatic brain injury. J Clin Sleep Med. 2007;3(4):349–56.
[PMID: 17694722]
2. Webster JB, Bell KR, Hussey JD, Natale TK, Lakshmi-
narayan S. Sleep apnea in adults with traumatic brain
injury: A preliminary investigation. Arch Phys Med Rehabil.
2001;82(3):316–21. [PMID: 11245752]
DOI:10.1053/apmr.2001.20840
3. Wilde MC, Castriotta RJ, Lai JM, Atanasova S, Masel BE,
Kuna ST. Cognitive impairment in patients with traumatic
brain injury and obstructive sleep apnea. Arch Phys Med
Rehabil. 2007;88(10):1284–88. [PMID: 17908570]
DOI:10.1016/j.apmr.2007.07.012
4. Castriotta RJ, Lai JM. Sleep disorders associated with trau-
matic brain injury. Arch Phys Med Rehabil. 2001;82(10):
1403–6. [PMID: 11588744]
DOI:10.1053/apmr.2001.26081
5. Lee HB, Lyketsos CG, Rao V. Pharmacological manage-
ment of the psychiatric aspects of traumatic brain injury. Int
Rev Psychiatry. 2003;15(4):359–70. [PMID: 15276957]
DOI:10.1080/09540260310001606746
6. Gastaut H, Tassinari CA, Duron B. [Polygraphic study of
diurnal and nocturnal (hypnic and respiratory) episodal
manifestations of Pickwick syndrome]. Rev Neurol (Paris).
1965;112(6):568–79. French. [PMID: 5856212]
7. Guilleminault C, Tilkian A, Dement WC. The sleep apnea
syndromes. Annu Rev Med. 1976;27:465–84.
[PMID: 180875]
DOI:10.1146/annurev.me.27.020176.002341
8. Sleep-related breathing disorders in adults: Recommenda-
tions for syndrome definition and measurement techniques
in clinical research. The Report of an American Academy
of Sleep Medicine Task Force. Sleep. 1999;22(5):667–89.
[PMID: 10450601]
9. Krieger J, Mangin P, Kurtz D. [Respiratory changes during
sleep in healthy elderly subjects]. Rev Electroencephalogr
Neurophysiol Clin. 1980;10(2):177–85. French.
[PMID: 7209080]
DOI:10.1016/S0370-4475(80)80051-7
10. Carskadon MA, Dement WC. Respiration during sleep in
the aged human. J Gerontol. 1981;36(4):420–23.
[PMID: 7252072]
11. Ancoli-Israel S. Epidemiology of sleep disorders. Clin
Geriatr Med. 1989;5(2):347–62. [PMID: 2665916]
12. Victor LD. Obstructive sleep apnea. Am Fam Physician.
1999;60(8):2279–86. [PMID: 10593319]
13. Sullivan CE, Issa FG, Berthon-Jones M, Eves L. Reversal
of obstructive sleep apnoea by continuous positive airway
pressure applied through the nares. Lancet. 1981;1(8225):
862–65. [PMID: 6112294]
DOI:10.1016/S0140-6736(81)92140-1
14. Ancoli-Israel S, Kripke DF, Klauber MR, Mason WJ, Fell
R, Kaplan O. Sleep-disordered breathing in community-
dwelling elderly. Sleep. 1991;14(6):486–95.
[PMID: 1798880]
15. Verdi FJ Jr, Slanzi GL, Cohen SR, Powell R. Use of the
Branemark implant in the cleft palate patient. Cleft Palate
Craniofac J. 1991;28(3):301–303. [PMID: 1911819]
DOI:10.1597/1545-1569(1991)028<0325:UOTBII>2.3.CO;2
16. Parcell DL, Ponsford JL, Rajaratnam SM, Redman JR.
Self-reported changes to nighttime sleep after traumatic
brain injury. Arch Phys Med Rehabil. 2006;87(2):278–85.
[PMID: 16442985]
DOI:10.1016/j.apmr.2005.10.024
17. Trudel TM, Tyron WW, Purdum CM. Awareness of disabil-
ity and long-term outcome after traumatic brain injury.
Rehabil Psychol. 1998;43(4):267–81.
DOI:10.1037/0090-5550.43.4.267
18. Cohen-Zion M, Stepnowsky C, Marler PD, Shochat T,
Kripke DF, Ancoli-Israel S. Changes in cognitive function
associated with sleep disordered breathing in older people.
J Am Geriatr Soc. 2001;49(12):1622–27.
[PMID: 11843994]
DOI:10.1111/j.1532-5415.2001.49270.x
19. Aloia MS, Ilniczky N, Di Dio P, Perlis ML, Greenblatt DW,
Giles DE. Neuropsychological changes and treatment com-
pliance in older adults with sleep apnea. J Psychosom Res.
2003;54(1):71–76. [PMID: 12505557]
DOI:10.1016/S0022-3999(02)00548-2
20. Naegele B, Pepin JL, Levy P, Bonnet C, Pellat J, Feuerstein
C. Cognitive executive dysfunction in patients with obstruc-
tive sleep apnea syndrome (OSAS) after CPAP treatment.
Sleep. 1998;21(4):392–97. [PMID: 9646384]
21. Redline S, Strauss ME, Adams N, Winters M, Roebuck T,
Spry K, Rosenberg C, Adams K. Neuropsychological func-
tion in mild sleep-disordered breathing. Sleep. 1997;20(2):
160–67. [PMID: 9143077]
22. Décary A, Rouleau I, Montplaisir J. Cognitive deficits
associated with sleep apnea syndrome: A proposed neurop-
sychological test battery. Sleep. 2000;23(3):369–81.
[PMID: 10811381]
23. O’Hara R, Yesavage JA, Derouesne C. Therapeutic
approaches to age-associated neurocognitive disorders.
Dialogues Clin Neurosci. 2001;3(3):191–213.
24. Khaime TsB. [Role of craniocerebral trauma in the devel-
opment of Alzheimer’s disease]. Zh Nevropatol Psikhiatr
Im S S Korsakova. 1976;76(7):1028–32. Russian.
[PMID: 961285]
25. Uryu K, Laurer H, McIntosh T, Practicò D, Martinez D,
Leight S, Lee VM, Trojanowski JQ. Repetitive mild brain
trauma accelerates Abeta deposition, lipid peroxidation,
and cognitive impairment in a transgenic mouse model of
Alzheimer amyloidosis. J Neurosci. 2002;22(2):446–54.
[PMID: 11784789]
26. Blasko I, Beer R, Bigl M, Apelt J, Franz G, Rudzki D,
Ransmayr G, Kampfl A, Schliebs R. Experimental trau-
matic brain injury in rats stimulates the expression, produc-
tion and activity of Alzheimer’s disease beta-secretase
(BACE-1). J Neural Transm. 2004;111(4):523–36.
[PMID: 15057522]
DOI:10.1007/s00702-003-0095-6
27. Hartman RE, Laurer H, Longhi L, Bales KR, Paul SM,
McIntosh TK, Holtzman DM. Apolipoprotein E4 influences
amyloid deposition but not cell loss after traumatic brain
injury in a mouse model of Alzheimer’s disease. J Neurosci.
2002;22(23):10083–87. [PMID: 12451108]
28. Jellinger KA. Traumatic brain injury as a risk factor for
Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004;
75(3):511–12. [PMID: 14966185]
29. Szczygielski J, Mautes A, Steudel WI, Falkai P, Bayer TA,
Wirths O. Traumatic brain injury: Cause or risk of Alzhei-
mer’s disease? A review of experimental studies. J Neural
Transm. 2005;112(11):1547–64. [PMID: 15959838]
DOI:10.1007/s00702-005-0326-0
30. Ikonomovic MD, Abrahamson EE, Isanski BA, Wuu J,
Mufson EJ, DeKosky ST. Superior frontal cortex cholinergic
axon density in mild cognitive impairment and early
Alzheimer disease. Arch Neurol. 2007;64(9):1312–17.
[PMID: 17846271]
DOI:10.1001/archneur.64.9.1312
31. Amaducci LA, Rocca WA, Schoenberg BS. Origin of the
distinction between Alzheimer’s disease and senile demen-
tia: How history can clarify nosology. Neurology. 1986;
36(11):1497–99. [PMID: 3531918]
32. Gottlieb S. Head injury doubles the risk of Alzheimer’s dis-
ease. Brit Med J. 2000;321:1100.
33. Graves AB, White E, Koepsell TD, Reifler BV, Van Belle
G, Larson EB, Raskind M. The association between head
trauma and Alzheimer’s disease. Am J Epidemiol. 1990;
131(3):491–501. [PMID: 2405648]
34. Jellinger KA, Paulus W, Wrocklage C, Litvan I. Effects of
closed traumatic brain injury and genetic factors on the
development of Alzheimer’s disease. Eur J Neurol. 2001;
8(6):707–10. [PMID: 11784357]
DOI:10.1046/j.1468-1331.2001.00322.x
35. Lye TC, Shores EA. Traumatic brain injury as a risk factor
for Alzheimer’s disease: A review. Neuropsychol Rev.
2000;10(2):115–29. [PMID: 10937919]
DOI:10.1023/A:1009068804787
36. Mortimer JA, French LR, Hutton JT, Schuman LM. Head
injury as a risk factor for Alzheimer’s disease. Neurology.
1985;35(2):264–67. [PMID: 3969219]
37. O’Meara ES, Kukull WA, Sheppard L, Bowen JD, McCor-
mick WC, Teri L, Pfanschmidt M, Thompson JD, Schellen-
berg GD, Larson EB. Head injury and risk of Alzheimer’s
disease by apolipoprotein E genotype. Am J Epidemiol.
1997;146(5):373–84. [PMID: 9290497]
38. Schofield PW, Tang M, Marder K, Bell K, Dooneief G,
Chun M, Sano M, Stern Y, Mayeux R. Alzheimer’s disease
after remote head injury: An incidence study. J Neurol
Neurosurg Psychiatry. 1997;62(2):119–24.
[PMID: 9048710]
DOI:10.1136/jnnp.62.2.119
39. Broe GA, Henderson AS, Creasey H, McCusker E, Korten
AE, Jorm AF, Longley W, Anthony JC. A case-control
study of Alzheimer’s disease in Australia. Neurology. 1990;
40(11):1698–1707. [PMID: 2146525]
40. Chandra V, Kokmen E, Schoenberg BS, Beard CM. Head
trauma with loss of consciousness as a risk factor for
Alzheimer’s disease. Neurology. 1989;39(12):1576–78.
[PMID: 2586772]
41. Mehta KM, Ott A, Kalmijn S, Slooter AJ, Van Duijn CM,
Hofman A, Breteler MM. Head trauma and risk of dementia
and Alzheimer’s disease: The Rotterdam Study. Neurology.
1999;53(9):1959–62. [PMID: 10599765]
42. Plassman BL, Havlik RJ, Steffens DC, Helms MJ, New-
man TN, Drosdick D, Phillips C, Gau BA, Welsh-Bohmer
KA, Burke JR, Guralnik JM, Breitner JC. Documented
head injury in early adulthood and risk of Alzheimer’s dis-
ease and other dementias. Neurology. 2000;55(8):1158–66.
[PMID: 11071494]
43. Fleminger S, Oliver DL, Lovestone S, Rabe-Hesketh S,
Giora A. Head injury as a risk factor for Alzheimer’s disease:
The evidence 10 years on; A partial replication. J Neurol
Neurosurg Psychiatry. 2003;74(7):857–62.
[PMID: 12810767]
DOI:10.1136/jnnp.74.7.857
44. Mortimer JA, Van Duijn CM, Chandra V, Fratiglioni L,
Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K,
Rocca WA. Head trauma as a risk factor for Alzheimer’s
disease: A collaborative re-analysis of case-control studies.
EURODEM Risk Factors Research Group. Int J Epidemiol.
1991;20(Suppl 2):S28–35. [PMID: 1833351]
45. Bramlett HM, Dietrich WD. Neuropathological protection
after traumatic brain injury in intact female rats versus
males or ovariectomized females. J Neurotrauma. 2001;18(9):
891–900. [PMID: 11565601]
DOI:10.1089/089771501750451811
46. Yaffe K, Grady D, Pressman A, Cummings S. Serum estro-
gen levels, cognitive performance, and risk of cognitive
decline in older community women. J Am Geriatr Soc.
1998;46(7):816–21. [PMID: 9670866]
47. Jordan BD, Relkin NR, Ravdin LD, Jacobs AR, Bennett A,
Gandy S. Apolipoprotein E epsilon4 associated with chronic
traumatic brain injury in boxing. JAMA. 1997;278(2):
136–40. [PMID: 9214529]
DOI:10.1001/jama.278.2.136
48. Newman MF, Croughwell ND, Blumenthal JA, Lowry E,
White WD, Spillane W, Davis RD Jr, Glower DD, Smith
LR, Mahanna EP. Predictors of cognitive decline after car-
diac operation. Ann Thorac Surg. 1995;59(5):1326–30.
[PMID: 7733762]
DOI:10.1016/0003-4975(95)00076-W
49. Nicoll JA, Roberts GW, Graham DI. Apolipoprotein E
epsilon 4 allele is associated with deposition of amyloid
beta-protein following head injury. Nat Med. 1995;1(2):
135–37. [PMID: 7585009]
DOI:10.1038/nm0295-135
50. O’Hara R, Yesavage JA, Kraemer HC, Mauricio M, Fried-
man LF, Murphy GM Jr. The APOE epsilon4 allele is asso-
ciated with decline on delayed recall performance in
community-dwelling older adults. J Am Geriatr Soc. 1998;
46(12):1493–98. [PMID: 9848808]
51. Tang MX, Maestre G, Tsai WY, Liu XH, Feng L, Chung
WY, Chun M, Schofield P, Stern Y, Tycko B, Mayeux R.
Effect of age, ethnicity, and head injury on the association
between APOE genotypes and Alzheimer’s disease. Ann N
Y Acad Sci. 1996;802:6–15. [PMID: 8993479]
DOI:10.1111/j.1749-6632.1996.tb32593.x
52. Luukinen H, Viramo P, Herala M, Kervinen K, Kesäniemi
YA, Savola O, Wingvist S, Jokelainen J, Hillbom M. Fall-
related brain injuries and the risk of dementia in elderly
people: A population-based study. Eur J Neurol. 2005;12(2):
86–92. [PMID: 15679695]
DOI:10.1111/j.1468-1331.2004.00953.x
53. Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M,
Tsenter J, Babaey S, Yehuda B, Groswasser Z. Apolipoprotein
E-epsilon4 genotype predicts a poor outcome in survivors of
traumatic brain injury. Neurology. 1999; 52(2):244–48.
[PMID: 9932938]
54. Millar K, Nicoll JA, Thornhill S, Murray GD, Teasdale
GM. Long term neuropsychological outcome after head
injury: Relation to APOE genotype. J Neurol Neurosurg
Psychiatry. 2003;74(8):1047–52. [PMID: 12876232]
DOI:10.1136/jnnp.74.8.1047
55. Guo Z, Cupples LA, Kurz A, Auerbach SH, Volicer L,
Chui H, Green RC, Sadovnick AD, Duara R, DeCarli C,
Johnson K, Go RC, Growdon JH, Haines JL, Kukull WA,
Farrer LA. Head injury and the risk of AD in the MIRAGE
study. Neurology. 2000;54(6):1316–23. [PMID: 10746604]
56. Jellinger KA, Paulus W, Wrocklage C, Litvan I. Traumatic
brain injury as a risk factor for Alzheimer disease. Compari-
son of two retrospective autopsy cohorts with evaluation of
ApoE genotype. BMC Neurol. 2001;1:3. [PMID: 11504565]
DOI:10.1186/1471-2377-1-3
57. Jellinger KA, Paulus W, Wrocklage C, Litvan I. Effects of
closed traumatic brain injury and genetic factors on the
development of Alzheimer’s disease. Eur J Neurol. 2001;
8(6):707–10. [PMID: 11784357]
DOI:10.1046/j.1468-1331.2001.00322.x
58. Mauri M, Sinforiani E, Bono G, Cittadella R, Quattrone A,
Boller F, Nappi G. Interaction between Apolipoprotein
epsilon 4 and traumatic brain injury in patients with Alzhei-
mer’s disease and mild cognitive impairment. Funct Neurol.
2006;21(4):223–28. [PMID: 17367583]
59. O’Meara ES, Kukull WA, Sheppard L, Bowen JD, McCor-
mick WC, Teri L, Pfanschmidt M, Thompson JD, Schellen-
berg GD, Larson EB. Head injury and risk of Alzheimer’s
disease by apolipoprotein E genotype. Am J Epidemiol.
1997;146(5):373–84. [PMID: 9290497]
60. Sundström A, Nilsson LG, Cruts M, Adolfsson R, Van
Broeckhoven C, Nyberg L. Fatigue before and after mild
traumatic brain injury: Pre-post-injury comparisons in rela-
tion to Apolipoprotein E. Brain Inj. 2007;21(10):1049–54.
[PMID: 17891567]
DOI:10.1080/02699050701630367
61. Isoniemi H, Tenovuo O, Portin R, Himanen L, Kairisto V.
Outcome of traumatic brain injury after three decades—
Relationship to ApoE genotype. J Neurotrauma. 2006;23(11):
1600–1608. [PMID: 17115907]
DOI:10.1089/neu.2006.23.1600
62. Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline
S, Givelber RJ, Young T. APOE epsilon4 is associated with
obstructive sleep apnea/hypopnea: The Sleep Heart Health
Study. Neurology. 2004;63(4):664–68. [PMID: 15326239]
63. Kadotani H, Kadotani T, Young T, Peppard PE, Finn L,
Colrain IM, Murphy GM Jr, Mignot E. Association
between apolipoprotein E epsilon4 and sleep-disordered
breathing in adults. JAMA. 2001;285(22):2888–90.
[PMID: 11401610]
DOI:10.1001/jama.285.22.2888
64. O’Hara R, Schröder CM, Kraemer HC, Kryla N, Cao C,
Miller E, Schatzberg AF, Yesavage JA, Murphy GM Jr.
Nocturnal sleep apnea/hypopnea is associated with lower
memory performance in APOE epsilon4 carriers. Neurology.
2005;65(4):642–44. [PMID: 16116137]
DOI:10.1212/01.wnl.0000173055.75950.bf
65. Gozal D, Capdevila OS, Kheirandish-Gozal L, Crabtree
VM. APOE epsilon 4 allele, cognitive dysfunction, and
obstructive sleep apnea in children. Neurology. 2007;69(3):
243–49. [PMID: 17636061]
DOI:10.1212/01.wnl.0000265818.88703.83
66. Cosentino FI, Bosco P, Drago V, Prestianni G, Lanuzza B,
Iero I, Tripodi M, Spada RS, Toscano G, Caraci F, Ferri R.
The APOE epsilon4 allele increases the risk of impaired
spatial working memory in obstructive sleep apnea. Sleep
Med. 2008;9(8):831–39. [PMID: 18083630]
DOI:10.1016/j.sleep.2007.10.015
67. Kalra M, Pal P, Kaushal R, Amin RS, Dolan LM, Fitz K,
Kumar S, Sheng X, Guha S, Mallik J, Deka R, Chakraborty
R. Association of ApoE genetic variants with obstructive
sleep apnea in children. Sleep Med. 2008;9(3):260–65.
[PMID: 17658295]
DOI:10.1016/j.sleep.2007.05.001
68. Bliwise DL, Friedman L, Nekich JC, Yesavage JA. Predic-
tion of outcome in behaviorally based insomnia treatments.
J Behav Ther Exp Psychiatry. 1995;26(1):17–23.
[PMID: 7642756]
DOI:10.1016/0005-7916(94)00073-U
69. Dunham CM, Ransom KJ, Flowers LL, Siegal JD, Kohli
CM. Cerebral hypoxia in severely brain-injured patients is
associated with admission Glasgow Coma Scale score,
computed tomographic severity, cerebral perfusion pres-
sure, and survival. J Trauma. 2004;56(3):482–89.
[PMID: 15128117]
DOI:10.1097/01.TA.0000114537.52540.95
70. Kemp AM, Stoodley N, Cobley C, Coles L, Kemp KW.
Apnoea and brain swelling in non-accidental head injury.
Arch Dis Child. 2003;88(6):472–76. [PMID: 12765909]
DOI:10.1136/adc.88.6.472
71. Rosner G. Combat hypoxia: The importance of airway
management & oxygenation of the traumatic brain injury
patient. JEMS. 2003;28(3):100–117; quiz 118–19.
[PMID: 12652281]
72. Schwartz DJ, Karatinos G. For individuals with obstructive
sleep apnea, institution of CPAP therapy is associated with
an amelioration of symptoms of depression which is sus-
tained long term. J Clin Sleep Med. 2007;3(6):631–35.
[PMID: 17993046]
73. Chang JJ, Youn TS, Benson D, Mattick H, Andrade N,
Harper CR, Moore CB, Madden CJ, Diaz-Arrastia RR.
Physiologic and functional outcome correlates of brain tissue
hypoxia in traumatic brain injury. Crit Care Med. 2009;
37(1):283–90. [PMID: 19050612]
DOI:10.1097/CCM.0b013e318192fbd7
74. Shea TB, Ortiz D, Rogers E. Differential susceptibility of
transgenic mice lacking one or both apolipoprotein alleles
to folate and vitamin E deprivation. J Alzheimers Dis.
2004;6(3):269–73. [PMID: 15201481]
75. Gozal E, Row BW, Schurr A, Gozal D. Developmental differ-
ences in cortical and hippocampal vulnerability to intermittent
hypoxia in the rat. Neurosci Lett. 2001;305(3):197–201.
[PMID: 11403939]
DOI:10.1016/S0304-3940(01)01853-5
76. Rami A, Volkmann T, Agarwal R, Schoninger S, Nürn-
berger F, Saido TC, Winckler J. Beta2-Adrenergic recep-
tor responsiveness of the calpain-calpastatin system and
attenuation of neuronal death in rat hippocampus after
transient global ischemia. Neurosci Res. 2003;47(4):
373–82. [PMID: 14630341]
DOI:10.1016/j.neures.2003.07.002
77. Moffat SD, Zonderman AB, Harman SM, Blackman MR,
Kawas C, Resnick SM. The relationship between longitudi-
nal declines in dehydroepiandrosterone sulfate concentra-
tions and cognitive performance in older men. Arch Intern
Med. 2000;160(14):2193–98. [PMID: 10904463]
DOI:10.1001/archinte.160.14.2193
78. Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S,
Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon
NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cum-
mings JL, Saunders AM, Pericak-Vance MA, Roses AD,
Barrio JR, Phelps ME. Cerebral metabolic and cognitive
decline in persons at genetic risk for Alzheimer’s Disease.
Proc Natl Acad Sci U S A. 2000;97(11):6037–42.
[PMID: 10811879]
DOI:10.1073/pnas.090106797
79. Soininen H, Partanen K, Pitkänen A, Hallikainen M, Hän-
ninen T, Helisalmi S, Mannermaa A, Ryynänen M,
Koivisto K, Riekkinen P Sr. Decreased hippocampal vol-
ume asymmetry on MRIs in nondemented elderly subjects
carrying the apolipoprotein E epsilon 4 allele. Neurology.
1995;45(2):391–92. [PMID: 7854548]
80. Hauri PJ. Sleep hygiene, relaxation therapy, and cognitive
interventions. Case studies in insomnia. New York (NY):
Plenum Medical Book; 1991. p. 65–84.
81. Stepanski EJ, Wyatt JK. Use of sleep hygiene in the treat-
ment of insomnia. Sleep Med Rev. 2003;7(3):215–25.
[PMID: 12927121]
DOI:10.1053/smrv.2001.0246
82. Young T, Blustein J, Finn L, Palta M. Sleep-disordered
breathing and motor vehicle accidents in a population-based
sample of employed adults. Sleep. 1997;20(8):608–13.
[PMID: 9351127]
83. Horstmann S, Hess CW, Bassetti C, Gugger M, Mathis J.
Sleepiness-related accidents in sleep apnea patients. Sleep.
2000;23(3):383–89. [PMID: 10811382]
84. Ellen RL, Marshall SC, Palayew M, Molnar FJ, Wilson
KG, Man-Son-Hing M. Systematic review of motor vehi-
cle crash risk in persons with sleep apnea. J Clin Sleep
Med. 2006;2(2):193–200. [PMID: 17557495]
85. Chesnut RM, Carney N, Maynard H, Patterson P, Mann
NC, Helfand M. Rehabilitation for traumatic brain injury.
Evid Rep Technol Assess (Summ). 1998;2:1–6.
[PMID: 11487799]
86. Robbins J, Redline S, Ervin A, Walsleben JA, Ding J, Nieto
FJ. Associations of sleep-disordered breathing and cerebral
changes on MRI. J Clin Sleep Med. 2005;1(2):159–65.
[PMID: 17561631]
87. Webster JB, Bell KR, Hussey JD, Natale TK, Lakshmi-
narayan S. Sleep apnea in adults with traumatic brain
injury: A preliminary investigation. Arch Phys Med Rehabil.
2001;82(3):316–21. [PMID: 11245752]
DOI:10.1053/apmr.2001.20840
88. Victor LD. Obstructive sleep apnea. Am Fam Physician.
1999;60(8):2279–86. [PMID: 10593319]
89. Ancoli-Israel S, Kripke DF. Prevalent sleep problems in the
aged. Biofeedback Self Regul. 1991;16(4):349–59.
[PMID: 1760457]
DOI:10.1007/BF00999989
90. Kreis P, Kripke DF, Ancoli-Israel S. Sleep apnea: A pro-
spective study. West J Med. 1983;139(2):171–73.
[PMID: 6636727]
91. Sharafkhaneh A, Giray N, Richardson P, Young T, Hirsh-
kowitz M. Association of psychiatric disorders and sleep
apnea in a large cohort. Sleep. 2005;28(11):1405–11.
[PMID: 16335330]
92. Mustafa M, Erokwu N, Ebose I, Strohl K. Sleep problems
and the risk for sleep disorders in an outpatient veteran popu-
lation. Sleep Breath. 2005;9(2):57–63. [PMID: 15875229]
DOI:10.1007/s11325-005-0016-z
93. Van Duijn CM, Tanja TA, Haaxma R, Schulte W, Saan RJ,
Lameris AJ, Antonides-Hendriks G, Hofman A. Head trauma
and the risk of Alzheimer’s disease. Am J Epidemiol. 1992;
135(7):775–82. [PMID: 1595677]

Submitted for publication October 14, 2008. Accepted in
revised form July 16, 2009.