REVIEW

URRENT
C
OPINION

Exploring the bi-directional relationship between

sleep and beta-amyloid
Belinda M. Brown a,b, Stephanie R. Rainey-Smith a,b, Romola S. Bucks c,
Michael Weinborn c, and Ralph N. Martins a,b

Purpose of review
Suboptimal sleep has been reported as both a comorbidity and risk factor for the development of
Alzheimers disease. Previous research suggests that beta-amyloid (Ab) may be central to this association,
with reports indicating a bi-directional relationship between sleep and Ab. Here, we review recent animal
and human studies investigating the relationship between sleep and measures of Ab, and explore the
potential mechanisms underlying this association.
Recent findings
Two recent animal studies have provided further support for a bi-directional relationship between sleep and
Ab. In addition, five recent human studies support the notion that higher brain Ab is linked to poor sleep in
cognitively healthy individuals. One of the recent human studies utilized polysomnography to link brain Ab
to a disruption in slow wave activity during sleep, which in turn was associated with decreased
hippocampal-dependent memory.
Summary
Recent findings indicate that poor sleep is a risk factor for brain Ab deposition, and Ab deposition
contributes to sleep disruption. Through the conduct of more mechanistic studies, and both longitudinal and
intervention human studies, we can further elucidate the clearly complex nature of the relationship between
sleep and Ab.
Keywords
Alzheimers disease, beta-amyloid, sleep

INTRODUCTION
Recent estimates indicate dementia affects 35.6
million people worldwide, with Alzheimers disease
accounting for 5070% of all cases [1]. Currently,
there is no pharmaceutical treatment that intervenes in the Alzheimers disease pathological cascade; thus, research attention has turned to
preventive measures, such as maintaining an
optimal lifestyle, to delay the onset of Alzheimers
disease. A relatively new candidate in this field of
research is sleep. Despite our vulnerability during
sleep, it is highly conserved in evolution, suggesting
that it serves a vital function. Evidence suggests that
sleep is critical both for tissue restoration [2] and the
clearance of brain metabolites, such as beta-amyloid
(Ab) [3]. The neuronal and synaptic loss consistent
with Alzheimers disease is proposed to be a consequence of Ab accumulation in the brain. Ab
accumulation occurs because of an imbalance in
the production and clearance of soluble Ab, which
leads to the aggregation of Ab into toxic oligomers

resulting in the deposition of Ab in plaque form [4].

Soluble Ab can be measured in cerebrospinal fluid
(CSF) and interstitial fluid (ISF), and has been validated as a proxy measure of insoluble Ab deposition
in the brain [5]. Insoluble Ab aggregates (comprising
extracellular senile plaques) in the brain can be
quantified using positron emission tomography
(PET) with the administration of an amyloidbinding ligand.

School of Medical and Health Sciences, Edith Cowan University,

Joondalup, Western Australia, Australia, bSir James McCusker Alzheimers Disease Research Unit, Hollywood Private Hospital, Nedlands,
Western Australia, Australia and cSchool of Psychology, University of
Western Australia, Nedlands, Western Australia, Australia
Correspondence to Belinda M. Brown, Building 11, Hollywood Private
Hospital, 115 Monash Avenue, Nedlands, WA 6009, Australia.
Tel: +61 8 6298 6314; e-mail: belinda.brown@ecu.edu.au
Curr Opin Psychiatry 2016, 29:397401
DOI:10.1097/YCO.0000000000000285

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Sleep disorders

KEY POINTS
 Recent animal studies have identified neuronal
excitability as a potential mediator of the relationship
between sleep and Ab.

relationship. Acute sleep deprivation (via infusion

of orexin, which promotes wakefulness) increases
levels of ISF Ab, and chronic sleep deprivation
increases Ab plaque formation in Alzheimers disease transgenic mice [6].
Recently, Liao et al. [12 ] investigated whether
acute and chronic manipulation of sleep using a
nonrapid eye moment (NREM) sleep-promoter
(growth hormone releasing hormone; GHRH)
was associated with ISF Ab (measured at 3 months)
and Ab deposition (measured at 7 months) in
Alzheimers disease transgenic mice. NREM sleep
was increased following acute GHRH administration, and this was associated with decreased
ISF Ab levels. Furthermore, inhibiting NREM sleep
using a GHRH antagonist increased ISF Ab,
suggesting a causal relationship; however, at the
age of 7 months (Ab deposition usually occurs at
approximately 6 months in these animal models)
these mice did not have significantly higher Ab
deposition, compared with the control mice.
Whilst this study provides further evidence that
the diurnal fluctuations of Ab are associated with
the sleep-wake cycle, more work is required to
identify the effect of chronic sleep disturbances
on insoluble Ab deposition. An important next
step in understanding the direction of the association between sleep and Ab will be identification
of mediating processes. One new candidate mediating mechanism is neuronal hyperexcitability.
Neuronal excitability has previously been
associated with the production of Ab through
enhanced cleavage of the amyloid precursor protein
(APP) [13]. Furthermore, though the function of
sleep remains to be fully elucidated, one strong
hypothesis is that sleep acts to decrease synaptic
strength; thus, prolonged wakefulness has been
associated with measures of cortical excitability.
Recent findings from Tabuchi et al. [14 ] suggest
neuronal excitability underlies the bi-directional
relationship between sleep and Ab. Using a Drosophilia (fruit fly) model of Alzheimers disease, the
authors report both chronic sleep deprivation and
Ab expression contribute to enhanced intrinsic
neuronal excitability. Furthermore, their findings
suggest that sleep deprivation worsens Ab-induced
hyperexcitability, and defects in specific K currents
(K current, sustained K current, and Ca2-activated K currents) underlie the hyperexcitability
caused by both sleep disruption and Ab. These findings suggest a positive feedback loop between sleep,
neuronal hyperexcitability and Ab, with preliminary work from this team suggesting that antiepileptic drugs may be important in targeting this
feedback loop in the early (preclinical) stages of
Alzheimers disease. Similarly, recent transgenic
&

 Recent human studies have further established a link

between sleep and brain Ab in cognitively
healthy individuals.
 Ab-induced sleep disruptions are associated with
decreases in hippocampal-dependent memory
in humans.
 Recent evidence supports the hypothesis that the
association between sleep and Ab is bi-directional.

Reports from animal research suggest Ab production and clearance is closely linked with the
sleep-wake cycle, with high extracellular levels of
Ab observed during wakefulness and low Ab levels
observed during sleep [6]. Human research has
revealed sleep-wake disturbances are a common
comorbidity of Alzheimers disease and recent evidence supports the hypothesis that increases in
circadian disorganization are associated with an
increase in severity of Alzheimers disease pathology
[7]. Importantly, it appears the association between
sleep and Ab is also evident in the earliest stages of
Alzheimers disease neuropathology. More specifically, reports from human studies suggest even in
the absence of cognitive impairments (i.e. studies of
cognitively healthy individuals), brain Ab deposition is associated with poorer sleep quality
[8,9,10 ]. In the current review, we have explored
the complex, likely bi-directional, relationship
between sleep and Ab, and have reviewed recent
studies of both animals and humans.
&&

&&

ANIMAL STUDIES OF SLEEP AND

BETA-AMYLOID
Previous animal work has established a link
between both soluble and insoluble (plaque) Ab
and sleep. Xie et al. [3] reported a 60% increase in
cortical interstitial space during sleep, which was
reflected by a marked increase in exchange of CSF
with ISF. The results from this study suggest that the
restorative function of sleep may be because of the
enhanced removal of toxic waste products, such as
Ab, that have accumulated during wakefulness.
Although these results suggest suboptimal sleep
contributes to increased Ab levels in the brain,
the same research group also reported that Ab disrupts the sleep-wake cycle of Alzheimers disease
transgenic mice [11], implying a bi-directional
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Exploring the bi-directional relationshi p between sleep and beta-amyloid Brown et al.
&

mouse model findings by Kam et al. [15 ] reveal large

transient spikes, resembling interictal spikes (IIS) on
EEG, occurring during sleep before the development
of Alzheimers disease neuropathology. IIS reflect
abnormal hyperexcitability and are a predominant
feature of epilepsy. Furthermore, IIS disrupt normal
sleep and may disturb the memory consolidation
function of sleep [16]. In the study by Kam et al., IIS
during REM sleep started at 5 weeks of age in Tg2576
mice (Alzheimers disease transgenic mice), and
increased in an age-dependent manner up to 3
months; wild type litter mates (age-matched) did
not exhibit signs of IIS at any age. To date, this is the
earliest report of in vivo hyperexcitability in these
particular mice. Nevertheless, as with previous
animal work investigating sleep and Ab, the direction of this association cannot be inferred: IIS may
increase Ab production, or Ab (prior to deposition)
could disrupt the normal activity of neurons, causing IIS and sleep disruption.
Animal studies offer the unique opportunity to
manipulate sleep regulation or Ab deposition; thus,
providing the greatest opportunities to understand
the directional association and the underlying
mechanisms of sleep and Ab. Importantly, should
animal studies be able to identify the initial
stimulus of this complex relationship, this information could be used in targeted intervention studies in humans.

HUMAN STUDIES OF SLEEP AND

BETA-AMYLOID
Human studies have provided intriguing evidence
to support the relationship between sleep and Ab,
which is facilitated by emerging techniques of
brain Ab measurement. Previously, using PET
with amyloid binding ligands, increased Ab burden in the brains of cognitively healthy individuals has been linked to poorer sleep quality [9].
Furthermore, decreased soluble Ab measurements
in CSF (reflecting increased brain Ab deposition)
have been associated with shorter sleep duration
and poorer sleep quality [8,17]. Recent studies
have continued to expand on the work in
this field with the link between sleep and Ab
in cognitively healthy individuals evident in
numerous reports.
Three recent amyloid PET imaging studies have
explored the relationship between self-reported
sleep parameters and brain Ab. Brown et al.
[10 ] examined the relationship between brain
Ab burden (quantified by three different amyloid-binding ligands with PET) and sleep factors
derived from the Pittsburgh Sleep Quality Index in
184 cognitively healthy individuals aged 60 years
&&

and older (mean age: 75.5  6.1). Longer sleep

latency (time taken to fall asleep) was associated
with higher neocortical brain Ab levels. Although
these cross-sectional findings should be interpreted with caution, this study suggests 30 min
longer sleep latency was equivalent to approximately 2 years of brain Ab accumulation. Other
sleep factors, such as sleep duration, sleep disturbances, sleep efficiency and daytime sleepiness were
not associated with brain Ab levels. This study also
examined the potential moderating effect of the
APOE e4 allele, revealing that this genetic risk
factor for Alzheimers disease did not influence
the relationship between sleep latency and brain
Ab in this cohort. Branger et al. [18 ] supported
the findings of Brown et al. in their study of 51
healthy older adults, reporting F18 Florbetapir PET
quantified Ab in prefrontal brain regions was
associated with longer sleep latency. Brain Ab
was not associated with any other sleep quality
factors. Increases in Ab in animal models have
been shown to disrupt the sleep-wake cycle [19],
thus, it is reasonable to hypothesize that longer
sleep latency may be a consequence of increased
brain Ab levels. Nevertheless, it cannot be discounted that longer sleep latency contributes to
increased Ab deposition, or, as previous animal
work demonstrates, that this association is the
product of a positive feedback loop. It is important
to note that the sleep parameters associated with
Ab levels have varied across studies. Indeed, in a
recent, comprehensive study of 98 cognitively
healthy older adults aged 5073 years, Sprecher
et al. [20 ] observed an association between less
adequate sleep, more sleep problems and greater
somnolence and increased Ab burden in the
angular gyrus, frontal medial orbital cortex, cingulate gyrus and precuneus, measured using C11 PiB
PET. Other sleep factors such as sleep duration,
sleep apnoea symptoms, trouble falling asleep
and daytime sleepiness (Epworth Sleepiness Scale)
were not associated with brain Ab.
An important next step in this field is to evaluate
levels of brain Ab against sleep parameters assessed
using gold standard measures, such as polysomnography (PSG) and actigraphy. Two recent, landmark
studies have utilized PSG to evaluate the relationship between objectively measured sleep parameters
and measurements of Ab in the brain and CSF. In a
study of 31 control participants and 10 participants
with obstructive sleep apnoea (OSA), Ju et al. [21 ]
reported NREM slow wave activity (SWA; a sign of
cortical neurons pausing synaptic plasticity) was
negatively correlated with CSF levels of Ab40 in
the control group; however, this relationship was
not observed in the (markedly smaller) OSA group.

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&&

&&

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399

Sleep disorders

Nevertheless, it must be noted that CSFAb40 is not a

core biomarker for Alzheimers disease [22]: stronger
correlates of Alzheimers disease neuropathology
such as CSFAb42 and tau were not correlated with
SWA. As expected, levels of CSF Ab42 were significantly lower (indicating increased brain Ab deposition) in the OSA group, compared to controls.
Finally, a recent study by Mander and colleagues
[23 ] investigated the relationship between sleep,
Ab and hippocampal-dependent memory. The
authors report, for the first time, that Ab in the
medial prefrontal cortex (measured by C11 PiB
PET) is associated with impairment of NREM
SWA. In addition, decreased NREM SWA is associated with impaired, overnight memory consolidation, and worsened hippocampal memory
transformation. Taken together, the findings from
these studies also support the notion of a positive
feedback loop linking sleep and Ab: the initial
emergence of Ab impairs NREM SWA, which in
turn contributes to wake-dependent increases in
Ab while reducing the sleep-associated clearance
of Ab.
&&

CONCLUSION
The recent research highlighted in this review provides further support for a relationship between
sleep and Ab. Although the literature evaluating
the association between sleep and Ab in humans
has been consistent over recent years, it remains
imperative that future work employs a longitudinal
approach utilizing gold standard measurements, for
example, via the tracking of PSG data and/or actigraphy data, combined with annual CSF Ab or amyloid PET scanning. Furthermore, interventional
trials utilizing cognitive behavioural therapy could
evaluate the impact of sleep changes on Ab changes
in the brain. In regard to animal work, although it
is becoming evident that the bi-directional hypothesis of sleep and Ab has strong research support,
little is known about the catalyst initiating this
association. The identification of mechanisms
underlying this association is essential. If researchers are able to identify the core, underlying mechanisms of the relationship between sleep and Ab,
this knowledge could be vital in informing the
development of targeted interventions for the early
stages of Alzheimers disease.
Acknowledgements
None.
Financial support and sponsorship
B.M.B. has received grant funding from Alzheimers
Australia Dementia Research Foundation and the
400

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NHMRC National Institute of Dementia Research.

S.R.S. has received grant funding from Brain Foundation
and Yulgilbar Foundation.
Conflicts of interest
There are no conflicts of interest.

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&&

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&&

This study reports Ab is associated with slow wave activity during NREM, and
reduced NREM slow wave activity impaired hippocampal-dependent memory
consolidation.

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