Evolution, Medicine, and Public Health [2017] pp. 39–46
doi:10.1093/emph/eow035
Does selection for short
sleep duration explain
human vulnerability to
Alzheimer’s disease?
Randolph M. Nesse,*
,1
Caleb E. Finch
2
and Charles L. Nunn
3
1
School of Life Sciences and Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85287, USA;
2
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA and
3
Department of Evolutionary Anthropology, Duke Global Health Institute, Duke University, Durham, NC 27708, USA
*Corresponding author. Randolph M. Nesse, Arizona State University, Tempe, AZ 85287, USA; E-mail: nesse@asu.edu
Received 31 August 2016; editorial decision 29 December 2016; revised version accepted 31 December 2016
ABSTRACT
Compared with other primates, humans sleep less and have a much higher prevalence of Alzheimer ’s
disease (AD) pathology. This article reviews evidence relevant to the hypothesis that natural selection
for shorter sleep time in humans has compromised the efficacy of physiological mechanisms that
protect against AD during sleep. In particular, the glymphatic system drains interstitial fluid from the
brain, removing extra-cellular amyloid beta (eAb) twice as fast during sleep. In addition, melatonin—a
peptide hormone that increases markedly during sleep—is an effective antioxidant that inhibits the
polymerization of soluble eAb into insoluble amyloid fibrils that are associated with AD. Sleep depriv-
ation increases plaque formation and AD, which itself disrupts sleep, potentially creating a positive
feedback cycle. These and other physiological benefits of sleep may be compromised by short sleep
durations. Our hypothesis highlights possible long-term side effects of medications that reduce sleep,
and may lead to potential new strategies for preventing and treating AD.
KEYWORDS: evolution; Alzheimer’s disease; sleep; glymphatic system; amyloid beta; melatonin
INTRODUCTION
Why are older humans distinctive among the apes in
their high prevalence of Alzheimer’s disease (AD)
[1]? The prevalence of AD increases exponentially
in humans, from under 2% at age 60 to about 40%
of individuals over age 90 [2]. Although its deleteri-
ous effects typically manifest too late in the life span
to have a major influence on Darwinian fitness
(reproductive success), the high prevalence of
this severely debilitating and often fatal
neurodegenerative brain disease in old humans,
and wide variations in the vulnerability of different
species, motivate us to seek an evolutionary explan-
ation [3–5].
In particular, among apes, humans are distinct-
ively vulnerable to the neuronal damage associated
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with AD [1,6], as initially hypothesized by Stanley
Rapoport [7]. While older great apes acquire modest
levels of amyloid beta (Ab) deposits at ages younger
than they are observed in humans, these amyloids
are typically diffuse and not associated with
degenerating neurons. In contrast, neuritic changes
and AD are commonly associated with plaques in
humans [1,8]. Humans are also outliers in their dra-
matically shorter sleep time compared to other pri-
mates, as discussed below. These two facts intersect
with new findings on the protective role of sleep to
suggest that selection for short sleep duration may
contribute to the distinctive human vulnerability to
AD.
AD is characterized by progressive cognitive def-
icits, especially of short-term memory, that are
associated with the loss of synapses and the death
of specific groups of neurons. The pathological hall-
marks of AD are gross shrinkage of the cerebral cor-
tex and the presence of fibrillar amyloid in neuritic
plaques, which are aggregates of Ab. The Ab peptide
is produced throughout life by neurons and is nor-
mally present in brain in interstitial and cerebro-
spinal fluid, as well as in the peripheral blood [9].
AD is also characterized by neurofibrillary tangles
of hyperphosphorylated tau protein within neurons.
The accumulation of brain amyloid fibrils and tau
pathology can be detected by PET imaging before
clinical grade dementia [10,11]. Neurofibrillary de-
generation typically spreads during clinical AD from
the medial temporal cortex into other cortical re-
gions, and subcortically into the hippocampus, a
key site of spatial memory; the earliest phase may
emanate from the brain stem locus coeruleus
[12,13]. While MRI comparisons of humans with
great apes reveal a relatively larger frontal lobe in
humans [14,15], neuroanatomical differences do
not readily explain the severe neurodegenerative
loss in humans during AD. Humans and other pri-
mates differ in patterns of gene expression in brain
pathways subject to neurodegeneration [8,16], yet
the amyloid peptide sequence is widely shared
across vertebrates, and is identical in humans and
primates [17].
Humans are also unique in their multiple
isoforms of apolipoprotein E (ApoE2,-3, and -4),
which differ in affinity for receptors and lipids,
whereas other primates have a single isoform, E4
[18–20]. ApoE4 is the major risk factor for AD, while
ApoE2 is AD-protective. Beside its role in blood chol-
esterol management, ApoE is important to the
homeostasis and remodeling of brain synapses.
ApoE4, which is considered the ancestral allele
[20], shows selective advantage in resistance to in-
fections [15].
Far from purely pathogenic, the amyloid precursor
protein (APP) is cleaved into several peptides with
diverse actions; some are neurotrophic, while others
are neurotoxic during development and throughout
life [21
]. A broader perspective is emerging on the
highly evolved functions of amyloid that go beyond
the initial Ab neurodegenerative cascade hypothesis
in AD [22–24]. In particular, the 2010 suggestion that
Ab has anti-microbial activity [25] has recently been
confirmed in studies showing that the expression of
Ab
40
or Ab
42
in cultured cells extends survival in the
presence of C. albicans, and that the expression of
Ab
42 in
in transgenic C. elegans extends survival in
the face of gut infection with C. albicans or
S. thyphimurium [16]. Furthermore, the presence of
microbes induces Ab precipitation in the mouse
brain within days, and Ab forms fibrils that entangle
fungi in a manner similar to other antimicrobial pep-
tides [16]. Antiviral actions of Ab have also been sug-
gested, in conjunction with evidence that viral
infections may contribute to AD [26].
HUMANS SLEEP LESS THAN OTHER
PRIMATES
Humans are also distinctive in their tendency to
sleep considerably less than other primates. In this
context, estimates of typical human sleep are crit-
ical: is the 8 h that sleep that physicians recommend
also a good estimate for ancestral average human
sleep duration? To address this question, re-
searchers are studying traditional human popula-
tions that lack access to electricity, and thus likely
have a stronger circadian drive based on natural
cycles of light and darkness. One recent study found
the average sleep times in three different hunter-
gatherer groups range from 5.7 to 7.1 h, with an over-
all average of 6.5 h [27]. Another set of authors
observed a nearly identical average sleep time for
agriculturalists in rural Madagascar [28], while a
study of a Haitian population lacking access to elec-
tricity identified the sleep duration as 7 h [29].
Notably, these studies used actigraphy, a method
that is known to overestimate sleep durations [30].
In addition, napping is less common than expected
in hunter-gatherers [27], yet perhaps more common
and longer in agriculturalists, potentially adding up
to an hour of sleep per day [28]. Taken together, 7 h is
a good upper-level estimate of typical human sleep,
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with many ancestral populations likely sleeping less
than this when ecological or social conditions con-
strain options for safe sleep. A meta-analysis
including 65 studies of 3577 subjects in Western
societies also found a 7.0 h average total sleep
time [31].
Using 7 h as a conservative estimate of the ances-
tral human sleep duration, humans are clearly short
sleepers relative to other primates (Fig. 1). Yet, is
this different from what one would expect for a diur-
nal primate with the body and brain size of a human?
Samson and Nunn [32] investigated human sleep
more quantitatively using a method that predicts a
phenotypic characteristic of a particular species
based on trait co-variation across the clade of inter-
est, phenotypic characteristics of the ‘target’ spe-
cies, and the phylogenetic placement of the
species of interest [33–35]. The implementation of
the method used by these authors is Bayesian, thus
producing a posterior probability distribution of pre-
dicted sleep duration in humans. With this posterior
distribution, one can compare the observed dur-
ation of sleep—7 h in this case—to the posterior
distribution of predictions. If humans lie below the
95% credible interval of values in the distribution,
they are determined to be a negative evolutionary
outlier (or a positive outlier if above the 95% credible
interval).
Using body mass, activity period, endocranial vol-
ume, percentage of leaves in the diet, interbirth inter-
val and foraging group size as predictor variables,
and a posterior distribution of primate evolutionary
trees from a Bayesian phylogenetic analysis [36],
Samson and Nunn’s [32] analysis predicted that that
humans should sleep for an astonishing average
of 10.3 h per night, with a 95% credible interval of
7.9–13.3 h per night. The conservative estimate of
7 h of sleep per night falls well below the 95% cred-
ible interval, suggesting that the average human
sleeps much less than predicted for a primate with
our phenotypic characteristics and the characteris-
tics of our close evolutionary relatives.
Several selective pressures involving the risks and
opportunity costs of sleep may have favored shorter
sleep in humans [32]. In terms of risks, one selection
pressure likely involved the transition from sleeping
in the trees to sleeping on the ground, where risk of
predation increased. While there is uncertainty
about the rates of predator attacks on current hunter
gatherers, predation rates for our ancestors were
likely high [39]. In addition to increased vulnerability
to predators, terrestrial sleep also makes humans
more vulnerable to hostile conspecifics, both within
the group and from other groups, because move-
ment and attacks may be easier at night when on
the ground.
Sleeping also imposes opportunity costs
including lost chances to socialize, to learn from
others or to learn through direct trial and error.
Individuals who sleep less could engage in more
social learning and social grooming, thus enhancing
learning and formation of alliances. Individuals who
sleep less could engage in more social learning and
social grooming, thus enhancing learning and for-
mation of alliances [40]. Interestingly, Samson and
Nunn [32] also found that the percentage of rapid eye
movement sleep (REM) was also higher than pre-
dicted for humans, which may enhance memory
consolidation, mental rehearsal of social and envir-
onmental challenges in dreams, and general prob-
lem-solving within the shorter period of human
sleep. Many of these phenomena would be beneficial
for learning and social alliance formation, and for
rehearsal of risks associated with terrestrial sleep.
LINKS BETWEEN SHORT SLEEP,
EVOLUTION AND AD
If selection for short sleep duration helps to explain
increased human vulnerability to AD, then sleep dis-
ruption should speed AD onset and progression,
mediated by definable and specific mechanisms.
Recent research has confirmed the physiologic ne-
cessity of sleep, documented the dire health conse-
quences of interrupted sleep and discovered several
Figure 1. Duration of total sleep time in primates, including
humans. Humans are the shortest sleeping primate (here,
using a value of 7 h, see text). The data on nonhuman primates
come from studies in which sleep was staged, most often by
EEG, in adult animals, and thus exclude some studies based
on videography [37] or studies of juvenile animals [38]
Evolution, short sleep duration, and Alzheimer’s disease Nesse et al. |41
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mechanisms that may mediate this relationship. We
discuss each of these in turn.
The utility of sleep
Sleep deprivation has well documented deleterious
effects on health [41]. The need for sleep is a cross-
species universal: extensive evidence confirms its
necessity despite the costliness of sleep in terms
of reduced vigilance [42]. Rats forced to stay awake
are more vulnerable to bacterial infections and
tumor growth [43]. It is broadly assumed that sleep
facilitates repair of tissue wear-and-tear from daily
activity because of severe health consequences of
sleep-deprivation. Humans with fatal familial in-
somnia and other ‘circadian disruptions’ have
higher mortality from diverse morbidities that im-
pact mental and physiological functions [44,45].
Sleep and AD
The role of sleep disruption in AD pathogenesis is
difficultto assess because AD itself is associated with
sleep disruption, as analyzed in humans and mouse
models by David Holtzman and colleagues [46]. With
this caveat in mind, self-reported sleep disturbance
at age 70 in a large prospective sample of men
showed 3-fold higher subsequent risk of AD, whereas
sleep disturbance at age 50 did not influence risk [47].
A large prospective study found increased risk of
compromised cognitive function for individuals
who had previously reported fewer than 6 or more
than 8 h of average sleep. However, the study also
found worse health for those at the extremes, so the
causal direction is unclear [48]. Moreover, in a very
recent prospective study of a large sample of cogni-
tively normal subjects followed for development of
subsequent AD (National Alzheimer Coordinating
Center), those with sleep disturbances had 3.4-fold
higher risk of subsequent AD; this risk ratio was fur-
ther increased by including BMI and APOE genotype
as covariates, suggesting that sleep is an independ-
ent risk factor for AD [49]. Both reports are consistent
with data showing greater Ab accumulations
measured via PET scan in those with shorter sleep
in a community sample [50].
Sleep deprivation of mice also slightly increased
Ab in brain interstitial fluid [51]. Cross-sectional and
longitudinal studies suggest that sleep disruption
can be a cause and an effect of AD [46,52].
Holtzman’s group is generating further data which
suggests a positive feedback cycle of sleep
disruption that could accelerate neurodegeneration
during AD [46,53]. On the positive side, sleep induc-
tion decreased axonal injury in a rat model of trau-
matic brain injury [54], and sleep may more generally
reduce AD-related neuropathology [55].
THE GLYMPHATIC SYSTEM
Recent research identifies some of the mechanisms
underlying the utility of sleep and its potential connec-
tion to AD. The brain has a specialized lymphatic system
involving astroglial cells, the ‘glymphatic system’, that
channels interstitial fluids in the brain through astro-
cytes into the peripheral lymphatic system [56–59].
The glymphatic system is especially relevant to AD be-
cause it transports Ab and metabolites out of the brain.
The connection to sleep is also strong, as the Ab trans-
port rate is doubled during sleep [59]. This has led some
scientists to hypothesize that insufficient sleep may be a
vital factor in the progression of AD [57–60]. Disruption
of glymphatic transport by inadequate sleep might also
mediate other effects on AD. For instance, traumatic
brain injury (TBI) often causes severe sleep disruption
that may contribute to the premature development of
amyloid plaques and tangles [61,62].
Aging may also impair glymphatic transport, as
suggested by the 40% decreased clearance of brain
Ab in older mice [63]. Differences between species also
provide useful evidence for a role for the glymphatic
system removing metabolic products. A comparative
study of cortical neuronal density in 24 mammalian
species found an inverse correlation of sleep duration
with the extra-cellular diffusion space. This finding was
interpreted as an outcome of selection for the capacity
to clear metabolites while maximizing the number of
hours awake for foraging [64]. In related work, Barton
and Capellini suggest that human sleep may have be-
come more efficient because the risks of sleeping on
the ground make it so costly [65].
MELATONIN
MEL may also influence rates of AD progression.
Levels of this potent antioxidant hormone increase
more than ten-fold in darkness and in association
with sleep onset. Reduced MEL levels, because of
lack of sleep or sleeping with lights on, increases
the risk of breast cancer [66], as confirmed in mice
[67]. Levels are reduced in the CSF of patients with
AD, and levels decrease further with disease progres-
sion [68]. The anti-inflammatory actions of melatonin
are consistent with extensive evidence for the
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possible role of inflammation in the pathogenesis of
AD. MEL has not only anti-inflammatory functions,
but can also directly inhibit the in vitro fibrillization of
Ab [69,70].By NMR spectrometry, MEL binds to Ab at
a single low affinity binding site, allowing the joint
clearance of MEL-Ab complexes [71]. In mice, mela-
tonin protected against the neurotoxicity of Ab [72],
whereas administered MEL had several effects that
decrease Ab production [73]. In vitro,Ab directly in-
hibits MEL production in mouse pineal cells in vitro.
CONCLUSIONS
Collectively, these emerging findings document a
role for sleep disruption in the pathogenesis of AD
that supports our suggestion that selection for short
sleeping time in humans may have made humans
more susceptible to AD. We do not propose that the
emergence of AD in human evolution has influenced
Darwinian fitness. Fitness impacts are possible after
the end of reproduction via kin selection, but they are
unlikely in this case because AD is rarely manifested
until after age 60, when selective forces on individ-
uals are weaker. We consider AD to be an epiphe-
nomenon of selection acting on other traits,
focusing here on the trade-off between the special
benefits for humans of reduced sleep time, and the
associated costs, including decreased protection of
the brain from AD and other kinds of damage.
While the data and recent findings generally point
toward a link between the evolution of short sleep
and AD in humans, we also wish to point out several
caveats and limitations. First, the effects of vari-
ations in sleep for individuals within a species do
not prove the effects of variations in sleep duration
across species. In the several million years since the
divergence of humans from our last common ances-
tor with other primates, selection may have adapted
the sleep system to function more efficiently [65].
Second, while the proposed short-term social and
safety benefits from shorter sleeping times are
plausible, they have not yet been documented in
humans. Data are also not yet available about pos-
sible social or physical disadvantages experienced
by hunter gathers who sleep less than others, topics
ripe for more research.
Third, the short sleep duration in humans could
have other explanations; for example, changes in
brain physiology associated with selection on cogni-
tive function could increase sleep efficiency, result-
ing in less need for sleep. We must also consider why
Ab accumulations (but not dying neurons) appear
years earlier in the brains of other primates
compared to humans [1,17], who sleep much less.
Fourth, the brain differences that make humans
more vulnerable to neuron damage are not direct re-
sults of Ab accumulation. Neuronal damage instead
seems to require interactions with immune mechan-
isms [74], which also mediate neuron pruning in the
normal course of development [75]. Of special interest
are aspects of innate immune function, particularly
CD33, a receptor that regulates Ab uptake by microglia
and has uniquely evolved alleles in humans [76].
Strong selection on these systems in the course of
rapid brain evolution offers an alternative explanation
for the distinctive human vulnerability to AD [3].
Another important unansweredquestioniswhether
glymphatic function, and the more general physio-
logical protection provided by sleep, vary considerably
among individuals, and whether such variations are
correlated with perceived need for sleep. If organisms
have mechanisms that monitor the concentrations of
brain metabolic products and modulate sleep need
accordingly, then those who thrive on fewer hours of
sleep are doubly fortunate. However, if maintenance of
brain integrity is proportional to the absolute number
of hours of sleep, healthy people who need less sleep
maybemorevulnerabletoAD.Weareunabletofind
reliable data on this point, but nonhuman animal
studies of the effects of sleeptimevariationsarepos-
sible. Also needed are studies of how glymphatic func-
tion, plaque formation and AD progression are
influenced by new drugs that reduce the need for sleep.
acknowledgements
We thank David Samson, Diego Mastroeni and Cynthia
Stonnington for comments on the manuscript. RMN thanks
Cynthia Stonnington for encouraging an evolutionary investiga-
tion into Alzheimer’s disease, and the ASU Center
(http://evmed.asu.edu) for Evolution and Medicine for support.
funding
CEF is grateful for support from the Cure Alzheimer’s Fund and
the National Institutes for Health (R01 AG051521, CE Finch;
P01 AG05142-31, H. Chui) and for encouragement by the
Center for Academic Research and Training in Anthropogeny
(CARTA) at the University of California San Diego.
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