Sleep disruptions during middle age may be a potential biomarker for developing Alzheimer’s disease later in life


People who report a declining quality of sleep as they age from their 50s to their 60s have more protein tangles in their brain, putting them at higher risk of developing Alzheimer’s disease later in life, according to a new study by psychologists at the University of California, Berkeley.

The new finding highlights the importance of sleep at every age to maintain a healthy brain into old age.

“Insufficient sleep across the lifespan is significantly predictive of your development of Alzheimer’s disease pathology in the brain,” said the study’s senior author, Matthew Walker, a sleep researcher and professor of psychology.

“Unfortunately, there is no decade of life that we were able to measure during which you can get away with less sleep.

There is no Goldilocks decade during which you can say, ‘This is when I get my chance to short sleep.’”

Walker and his colleagues, including graduate student and first author Joseph Winer, found that adults reporting a decline in sleep quality in their 40s and 50s had more beta-amyloid protein in their brains later in life, as measured by positron emission tomography, or PET.

Those reporting a sleep decline in their 50s and 60s had more tau protein tangles.

Both beta-amyloid and tau clusters are associated with a higher risk of developing dementia, though not everyone with protein tangles goes on to develop symptoms of dementia.

Based on the findings, the authors recommend that doctors ask older patients about changes in sleep patterns and intervene when necessary to improve sleep to help delay symptoms of dementia.

This could include treatment for apnea, which leads to snoring and frequent halts in breathing that interrupts sleep, and cognitive behavioral therapy for insomnia (CBT-I), a highly effective way to develop healthy sleep habits.

It may even include simple sleep counselling to convince patients to set aside time for a full eight hours of sleep and simple sleep hygiene tricks to accomplish that.

“The idea that there are distinct sleep windows across the lifespan is really exciting.

It means that there might be high-opportunity periods when we could intervene with a treatment to improve people’s sleep, such as using a cognitive behavioral therapy for insomnia,” Winer said.

“Beyond the scientific advance, our hope is that this study draws attention to the importance of getting more sleep and points us to the decades in life when intervention might be most effective.”

The 95 subjects in the study were part of the Berkeley Aging Cohort Study (BACS), a group of healthy older adults — some as old as 100 years of age — who have had their brains scanned with PET, the only technique capable of detecting both beta-amyloid tangles and, very recently, tau tangles, in the brain.

Winer, Walker and their colleagues reported their results online last week in the Journal of Neuroscience.

Brain waves out of sync

The team also made a second discovery.

They found that people with high levels of tau protein in the brain were more likely to lack the synchronized brain waves that are associated with a good night’s sleep.

The synchronization of slow brain waves throughout the cortex of the sleeping brain, in lockstep with bursts of fast brain waves called sleep spindles, takes place during deep or non-rapid eye movement (NREM) sleep.

The team reported that the more tau protein older adults had, the less synchronized these brain waves were.

This impaired electrical sleep signature may, therefore, act as a novel biomarker of tau protein in the human brain.

“There is something special about that synchrony,” given the consequences of this tau protein disruption of sleep, Walker said.

“We believe that the synchronization of these NREM brain waves provides a file-transfer mechanism that shifts memories from a short-term vulnerable reservoir to a more permanent long-term storage site within the brain, protecting those memories and making them safe.

But when you lose that synchrony, that file-transfer mechanism becomes corrupt. Those memory packets don’t get transferred, as well, so you wake up the next morning with forgetting rather than remembering.”

Indeed, last year, Walker and his team demonstrated that synchronization of these brain oscillations helps consolidate memory, that is, hits the “save” button on new memories.

Several years ago, Walker and his colleagues initially showed that a dip in the amplitude of slow wave activity during deep NREM sleep was associated with higher amounts of beta-amyloid in the brain and memory impairment.

Combined with these new findings, the results help identify possible biomarkers for later risk of dementia.

“It is increasingly clear that sleep disruption is an underappreciated factor contributing to Alzheimer’s disease risk and the decline in memory associated with Alzheimer’s,” Walker said.

“Certainly, there are other contributing factors: genetics, inflammation, blood pressure. All of these appear to increase your risk for Alzheimer’s disease.

But we are now starting to see a new player in this space, and that new player is called insufficient sleep.”

The brain rhythms were recorded over a single eight-hour night in Walker’s UC Berkeley sleep lab, during which most of the 31 subjects wore a cap studded with 19 electrodes that recorded a continual electroencephalogram (EEG). All had previously had brain scans to assess their burdens of tau and beta-amyloid that were done using a PET scanner at the Lawrence Berkeley National Laboratory and operated by study co-author William Jagust, professor of public health and a member of Berkeley’s Helen Wills Neuroscience Institute.

Is sleep a biomarker for dementia?

Doctors have been searching for early markers of dementia for years, in hopes of intervening to stop the deterioration of the brain.

Beta-amyloid and tau proteins are predictive markers, but only recently have they become detectable with expensive PET scans that are not widely accessible.

Yet, while both proteins escalate in the brain in old age and perhaps to a greater extent in those with dementia, it is still unknown why some people with large burdens of amyloid and tau do not develop symptoms of dementia.

“The leading hypothesis, the amyloid cascade hypothesis, is that amyloid is what happens first on the path to Alzheimer’s disease.

Then, in the presence of amyloid, tau begins to spread throughout the cortex, and if you have too much of that spread of tau, that can lead to impairment and dementia,” Winer said.

Walker added that “A lack of sleep across the lifespan may be one of the first fingers that flicks the domino cascade and contributes to the acceleration of amyloid and tau protein in the brain.”

The hypothesis is supported, in part, by Jagust’s PET studies, which have shown that higher levels of beta-amyloid and tau protein tangles in the brain are correlated with memory decline, tau more so than amyloid.

Tau occurs naturally inside the brain’s neurons, helping to stabilize their internal skeleton.

With age, tau proteins seem to accumulate inside cells of the medial temporal lobe, including the hippocampus, the seat of short-term memory. Only later do they spread more widely throughout the cortex.

This shows a brain with tau deposits marked

Greater levels of pathological tau protein, primarily in the brain’s medial temporal lobe (orange and yellow at bottom in cross section of the brain), were associated with weaker synchrony of slow waves (red) and sleep spindles (orange), two brain waves important for storing memories while we sleep. The image is credited to UC Berkeley image by Matthew Walker and Joseph Winer.

While Jagust has run PET scans on the brains of many healthy people, as well as those with dementia, many more subjects are needed to confirm the relationship between protein tangles and dementias like Alzheimer’s disease.

Because PET scanners are currently expensive and rare, and because they require an injection of radioactive tracers, other biomarkers are needed, Walker said.

The new study suggests that sleep changes detectable in a simple overnight sleep study may be less intrusive biomarkers than a PET scan.

“As wearable technology improves, this need not be something you have to come to a sleep laboratory for,” said Walker.

“Our hope is that, in the future, a small head device could be worn by people at home and provide all the necessary sleep information we’d need to assess these Alzheimer’s disease proteins. We may even be able to track the effectiveness of new drugs aimed at combating these brain proteins by assessing sleep.”

“I think the message is very clear,” Walker added.

“If you are starting to struggle with sleep, then you should go and see your doctor and find ways, such as CBT-I, that can help you improve your sleep. The goal here is to decrease your chances of Alzheimer’s disease.”

Other study co-authors are Bryce Mander, a former Berkeley postdoctoral researcher now at UC Irvine; Randolph Helfrich, Theresa Harrison, Suzanne Baker and Robert Knight of UC Berkeley and Anne Maass, a former Berkeley postdoctoral researcher at the German Center for Neurodegenerative Diseases.

Sleep plays a crucial role in the continuity of cognitive sequences and executive functions. Sleep deprivation is a common complaint in modern societies. Insufficient sleep has increased the risk of catching some diseases such as Alzheimer Disease (AD).

It is a type of dementia that causes problems with memory, thinking, and behavior. Symptoms usually develop slowly and get worse over time, becoming severe enough to interfere with daily task. AD is the most common cause of dementia, a general term for memory loss and other cognitive disabilities serious enough to interfere with daily life. Alzheimer disease accounts for 60% to 80% of dementia cases.

AD worsens over time, where dementia symptoms gradually worsen over a number of years. In its early stages, memory loss is mild, but with late-stage, individuals lose the ability to carry on a conversation and respond to their environment.

AD is the sixth leading cause of death in the United States.

Those with Alzheimer live an average of eight years after their symptoms become noticeable to others, but survival can range from 4 to 20 years, depending on age and other health conditions. Losing just one night of sleep led to an immediate increase in beta-amyloid, a protein in the brain associated with Alzheimer disease.

The biological and behavioral roles of sleep are not entirely elucidated. Studies show that sleep plays a crucial role in the continuity of cognitive sequences and executive functions (Cirelli, Shaw, Rechtschaffen, & Tononi, 1999Wilckens, Woo, Kirk, Erickson, & Wheeler, 2014). Sleep Deprivation (SD) as a common phenomenon in the modern societies, endangers individuals‘ health both in acute and chronic states.

The reduced sleep hours is related to alterations in living style, increase in night work hours, and late-night activities (Navara & Nelson, 2007). Studies show that people with insomnia or sleep disorders are at elevated risk for neuro-degenerative disorders such as Alzheimer Disease (AD) (Cedernaes et al., 2016).

Moreover, SD are observed across moderate to severe AD and are worsened with the progression of the disease (Anderson & Bradley, 2013).

Tau is one of the most important Microtubule Associated Proteins (MAP) in the neurons.

The balanced tau phosphorylation binds it to the microtubules, assembles the microtubules, and maintains the structure and stability of the neurons (Kadavath et al., 2015). However, hyperphosphorylation of tau results in its aggregation and formation of paired helical filamentous structures known as Neurofibrillary Tangles (NFTs) (Harrison & Owen, 2016).

NFTs are among the main neurological hallmarks of AD (Cox, Davis, Mash, Metcalf, & Banack, 2016).

Evidence from animal models illustrates that changes in the sleep-wake cycle may elevate hyperphosphorylated Tau protein in the brain (Di Meco, Joshi, & Praticò, 2014Rothman, Herdener, Frankola, Mughal, & Mattson, 2013).

It is reported that two months of SD causes more than 50% elevation of the insoluble Tau in the brain (Nunomura et al., 2001).

In addition, chronic SD increases extracellular amyloid, the main component of the amyloid plaques found in the brains of patients with Alzheimer (Sadigh-Eteghad et al., 2015) and sleep extension decreases plaques in animal models (Lim, Gerstner, & Holtzman, 2014).

It is indicated that Cerebrospinal Fluid (CSF) Amyloid-β (Aβ) levels predict amyloid plaque deposition, and sleep deprivation is associated with fluctuations in the level of  in CSF and its deposition in the brain (Roh et al., 2012); even one night of sleep deprivation is proposed to be associated with a 6% decrease in CSF Aβ42 levels (Ooms et al., 2014). Therefore, in general, it seems that SD can affect Alzheimer pathology through intermediate mechanisms.

The current study aimed at reviewing the most significant factors mediating between SD and AD including Apolipoprotein E (ApoE) risk alleles, kinases, and phosphatases dysregulation, reactive oxygen species, endoplasmic reticulum damage, glymphatic system dysfunction, and orexinergic system inefficacy. Obviously, studying these factors in an integrated and concise way can be useful for researchers in the field of sleep and Alzheimer pathology.

Apolipoprotein E Risk Alleles

ApoE, as the main component of chylomicrons and Intermediate-Density Lipoproteins (IDLs), plays an essential role in the normal catabolism of lipoproteins (Huang & Mahley, 2014). 

ApoEtransfers lipoproteins, fat-soluble vitamins, and cholesterol to the lymph vessels and then to the bloodstream.

It is originally synthesized in the liver, but it is also abundant in the Central Nervous System (CNS) (Mahley, 2016).

There are at least three variants (alleles) of the APOEgene, ε2ε3, and ε4 (Ryu, Atzmon, Barzilai, Raghavachari, & Suh, 2016).

APOE ε4 genetic variant is known as the main genetic risk determinant of AD. The ε4 allele also increases the risk for cerebral amyloid aggregation and age-related cognitive impairments (Liu, Kanekiyo, Xu, & Bu, 2013).

It is believed that APOE risk variants can activate specific intracellular pathways by binding to surface receptors and peptides of the neurons, which ultimately leads to neurodegeneration and synaptic dysfunction (Giau, Bagyinszky, An, & Kim, 2015). Furthermore, pathological influence of ApoE on increasing cerebral  deposition is demonstrated in several studies (Morris et al., 2010).

ApoE-lipoproteins, by removing the soluble  from the extracellular matrix, can facilitate its uptake through LRP1, LDLR, and HSPG receptors.

Additionally, the association between ApoE, 24S-hydroxycholesterol, and tau shows its direct involvement in generation of NFTs (Leoni, Solomon, & Kivipelto, 2010).

On the other hand, the association of APOE with sleep disorders is also proven.

For example, Kadotani et al. (2001) reported a significant relationship between sleep-disordered breathing and APOE ε4 variant in the general population and Tisko et al. (2014)reported that Obstructive Sleep Apnea (OSA) is associated with ε4 allele.

In addition, Lim et al., (2013) proposed that specific APOE ε4 genotypes may predispose individuals to sleep disruption and sleeping adequately inhibits the effect of ApoE on the formation of NFTs and progression of AD.

Kinases and Phosphatases Dysregulation

Protein kinases and phosphatases are two groups of enzymes that transfer phosphate to and from substrates such as tau protein (Cheng, Qi, Paudel, & Zhu, 2011Nichol, Parachikova, & Cotman, 2007).

Several protein kinases such as cyclic AMP-dependent Protein Kinase A (PKA), Calcium/calmodulin-dependent protein Kinase II (CaMKII), Glycogen Synthase Kinase-3β (GSK-3β), and Protein Phosphatases 2A (PP2A) have role in tau phosphorylation and de-phosphorylation (Shanavas & Papasozomenos, 2000).

PKA is one of the enzymes involved in sleep/wake regulation (Avila et al., 2012Hellman, Hernandez, Park, & Abel, 2010).

There is evidence that sleep deprivation causes PKA activation in the brain (Datta & Desarnaud, 2010Graves et al., 2003) and its activation increases phosphorylation in multiple sites of tau (Ittner et al., 2016).

CaMKII is a complex protein kinase and has an important role in synaptic plasticity and memory formation (Giese & Mizuno, 2013). Animal studies show that sleep deprivation remarkably dysregulates CaMKII-related phosphorylation (Cui et al., 2016). Furthermore, CaMKII is also a tau kinase and its dysregulation is associated with Alzheimer’s progression (Ghosh & Giese, 2015) and CaMKII inhibits tau-microtubule interaction by tau phosphorylation (Singh et al., 1996).

Evidence shows that GSK-3β is another enzyme that influences sleep-wake organization (Ahnaou & Drinkenburg, 2011Albrecht, 2012Hickie, Naismith, Robillard, Scott, & Hermens, 2013). This enzyme phosphorylates at least 36 residues of tau protein (Hanger et al., 2007).

As a matter of fact, GSK-3 activation is a critical step in brain aging and AD that triggers cascade of detrimental events such as NFT formation and neuronal death pathways (Takashima, 2006).

On the other hand, an Extra-cellular signal-Regulated Kinase (ERK) is centrally involved in memory consolidation process (Kelly, Laroche, & Davis, 2003). Phosphorylation of ERK is a key step to inhibit its activity in response to synaptic stimuli (Grewal, York, & Stork, 1999). 

Guan, Peng and Fang (2004) demonstrated that SD impairs ERK phosphorylation process in the hippocampus and this leads to spatial memory impairments in rats. Future studies may clarify the role of this protein in the relationship between sleep disorders and AD in humans.

Reactive Oxygen Species

Reactive Oxygen Species (ROS) are a number of molecular oxygen-derived reactive molecules and free radicals produced as byproducts during the mitochondrial electron transport or through oxidoreductase enzymatic activities (Ray, Huang, & Tsuji, 2012).

Recent works demonstrated that ROS have a role in cellular signaling cascades including apoptosis, cell cycle regulation, phagocytosis, enzyme activation, and gene expression.

The imbalance of ROS and antioxidant capacity of cells lead to oxidative stress (Dixon & Stockwell, 2014).

Generally, due to the higher metabolic rate and the low rate of regeneration, nerve cells are more susceptible to oxidative damage (Manoharan et al., 2016).

Studies show that inefficient antioxidant system and the excess of free radicals such as superoxide anion, hydrogen peroxide, and nitric oxide may be among the causes of the emergence of AD (Xie et al., 2002).

Positive association between the amyloid plaque and 4-hydroxynonenal and malondialdehyde as the main lipid peroxidation markers proves this hypothesis to some extent (Massaad, 2011).

Furthermore, it is demonstrated that iron accumulation in the brain of patients with AD is responsible for generating free radicals through the Fenton reaction (Zhao & Zhao, 2013). On the other hand, it is shown that SD can reduce the function of the antioxidant system of the cells. 

Ramanathan, Gulyani, Nienhuis and Siegel (2002) showed that prolonged sleep deprivation profoundly decreased superoxide dismutase antioxi-dative activity in the hippocampus and brainstem of rats.

Mathangi, Shyamala and Subhashini (2012) reported that paradoxical sleep deprivation was a potent oxidative stressor, which likely played a role in the behavioral changes of animal models. It is also shown in humans that SD can increase malondialdehyde (El-Helaly & Abu-Hashem, 2010).

Therefore, SD increases the oxidative stress and may thus contribute to the etiology of AD.

Endoplasmic Reticulum Damages

The Endoplasmic Reticulum (ER) is involved in folding and trafficking of proteins, redox homeostasis, energy production, and apoptosis (Cao & Kaufman, 2014).

Malfunctions of the ER may lead to a cell stress response, which can eventually trigger programmed cell death.

Increasing evidence emphasizes on the role of ER in the development and progression of neurodegenerative diseases (Scheper & Hoozemans, 2015). Studies indicate that apoptosis generally occurs through two main pathways: the death receptor (extrinsic) and the mitochondrial (intrinsic) pathways (Elmore, 2007).

ER stress has a key role in the pathogenesis of AD. Inositol-Requiring kinase 1 (IRE1) initiates the ER stress pathway by triggering Apoptosis Signal-regulating Kinase 1 (ASK1), which in turn activates c-Jun N-terminal Kinase (JNK) signaling route (Okazawa & Estus, 2002).

This cascade has the potential to trigger AD pathogenesis through dysregulation of Amyloid Precursor Protein (APP) processing and intracellular  accumulation, activation of Activator Protein 1 (AP-1), a transcription factor that regulates inflammatory genes expression, and hyperphosphorylation of tau protein, and aggregation of neurofibrillary tangles (Viana, Nunes, & Rodrigues, 2012).

Also, ER stress causes deposition of unfolded or misfolded proteins such as tau (Kanemoto & Wang, 2012Naidoo, 2009). Prolonged presence of these toxic unfolded proteins triggers intrinsic apoptosis pathways (Fribley, Zhang, & Kaufman, 2009).

Degradation of tau decreased by 20% in ER stress due to decrease in the binding of tau to CHIP (carboxyl terminus of Hsc70-interacting protein), which delayed the degradation of tau through the ubiquitin-proteasome pathway. SD increases ER stress in brain tissue (Sakagami et al., 2013).

It is proposed that REM SD elevates the level of noradrenaline in the brain (Ranjan, Biswas, & Mallick, 2010).

Animal studies indicate that REM SD changes BAX and Bcl2 functions and initiate mitochondrial apoptosis pathway (Ranjan et al., 2010). Somarajan, Khanday and Mallick (2016) suggested that elevated noradrenaline acting on α1-adrenergic receptor causes mitochondrial damage, release of cytochrome c, and induction of apoptosis intrinsic pathway.

Therefore, SD can be related to the Alzheimer’s pathology through induction of neuronal apoptosis.

Glymphatic System Dysfunctions

Iliff et al. (2012) discovered the dynamic characteristics of the glymphatic system in mice, using in vivo two-photon microscopy.

By fluorescent labeling of CSF, they showed the rapid entry of CSF into the brain along the cortical and pial arteries, following the influx into the Virchow-Robin spaces through penetrating arterioles. In fact, the CSF enters the parenchyma through a definite periarterial pathway surrounded by perivascular astrocytic end-feet (Iliff et al., 2012).

It can be concluded that glymphatic system plays a key role in feeding the neurons and purgation of the brain environment.

Glymphatic system works differently during sleep and awakening.

It is hypothesized that during the sleep, the CSF flows more profusely and the elimination of toxic substances from neurons and intercellular spaces is greatly increased.

When sleep is restricted, glymphatic system does not have enough time to fulfill its function; hence, toxins and misfolded proteins are accumulated, and the effects will appear in cognitive capabilities and executive functions (Eugene & Masiak, 2015).

On the other hand, Weller et al. (2008) demonstrated that macroscopic glymphatic system-based clearance of interstitial metabolites may be of particular significance for neurodegenerative diseases such as AD, in which, the accumulation of protein aggregates is observed (Iliff et al., 2012).

In this regard, Iliff et al. (2012) found that  was rapidly broken down and eliminated in the glymphatic system route.

In other words, imbalance between  production and clearance can result in accumulation of  and emergence of AD. As a result, SD may be associated with a decrease in the ability of the glymphatic system and an increase in the accumulation of  and Alzheimer etiology.

Orexinergic System Inefficacy

The orexins (hypocretins), as hypothalamic neuropeptides, play an important role in sleep-wake cycle regulation (Sakurai, Pandi-Perumal, & Monti, 2015).

Abnormal levels of these neuropeptides in people with sleep disorders led to research into its role in sleep regulation (Ebrahim, Howard, Kopelman, Sharief, & Williams, 2002).

In humans, orexinergic neurons are restricted to the dorsolateral hypothalamus, and project densely to various regions such as the Locus Coeruleus (LC), amygdala, suprachiasmatic nucleus, dorsal raphe nuclei, and cholinergic brainstem (Mieda & Sakurai, 2016).

Although the role of the orexinergic system in sleep regulation is not certainly known, however, it is believed that orexinergic projections modulate cholinergic and monoaminergic activities during the sleep cycle.

Indeed, inputs from suprachiasmatic nucleus to the orexinergic system exhibit the dependence of this system function on the dark-light cycle (Hungs & Mignot, 2001). Studies show a significant reduction in the number of orexinergic neurons in human narcolepsy (Mieda & Sakurai, 2016).

Mehta, Khanday and Mallick (2015) measured orexin-A level in LC, cortex, posterior hypothalamus, hippocampus, and pedunculopontine areas after 96 hours REM SD in rats. They reported that following the REM SD, the orexin-A level significantly increased in LC, cortex, and posterior hypothalamus.

Interestingly, they observed that after recovery, the level of orexin-A returned to its normal state.

On the other hand, it is demonstrated that increase in orexin due to chronic SD is involved in the pathogenesis of AD (Scammell, Matheson, Honda, Thannickal, & Siegel, 2012). Liguori et al. (2014) illustrated that patients with moderate-to-severe AD had higher levels of orexin and faced higher levels of nocturnal sleep disorders. In addition, it is proposed that orexin-A is associated with increased phosphorylated tau and this may be related to a reduction in the ratio of deep sleep (Osorio et al., 2016).

Funding: The work is supported by the National Institutes of Health (R01AG031164, RF1AG054019, RF1AG054106, F32AG057107).

UC Berkeley
Media Contacts: 
Robert Sanders – UC Berkeley
Image Source:
The image is credited to UC Berkeley image by Matthew Walker and Joseph Winer.

Original Research: Closed access
“Sleep as a potential biomarker of tau and β-amyloid burden in the human brain”. Joseph R. Winer, Bryce A. Mander, Randolph F. Helfrich, Anne Maass, Theresa M. Harrison, Suzanne L. Baker, Robert T. Knight, William J. Jagust and Matthew P. Walker.
Journal of Neuroscience. doi:10.1523/JNEUROSCI.0503-19.2019



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