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Investigators reported that acute sleep loss alters diurnal profiles of plasma-based Alzheimer's disease biomarkers in the cerebrospinal fluid of healthy young men.

Blood serum levels of a protein linked to Alzheimer's disease (AD)total tau (t-tau)rose significantly after just one night of acute sleep loss in healthy young men, according to a new report published in the January 8 online edition of Neurology.

What is notable is that the present and similar findings have been demonstrated in young, healthy individuals, study investigator and author Jonathan Cedernaes, MD, PhD, told Neurology Today. Taken together with evidence that sleep loss at an earlier age seems to be somewhat predictive of the risk of later developing Alzheimer's disease, we believe this at least provides an indication that even young individuals should take care of their sleep.

Dr. Cedernaes noted that the evidence suggests it may also be important for those who are already at risk for AD due to genetic factors, for instance, to optimize their sleep.

One should also not forget that many other factors can be important for prevention of AD, such as diet and exercise, so all of these factors need to be considered to promote a healthy lifestyle in general, he added.

Dr. Cedernaes, a senior researcher in the neuroscience department at Uppsala University in Sweden, and his colleagues conducted a within-subject, crossover-design study with 15 healthy men in their early 20s who participated in two standardized in-lab sessions with two different conditionsone night of normal sleep and one night of overnight sleep deprivation. The researchers then measured levels of t-tau and another biomarker of AD, amyloid beta (Abeta-40 and Abeta-42), before and after each overnight session. In addition, in order to investigate biomarkers of neuroaxonal injury, the researchers also assessed levels of neurofilament light chain (NfL), a protein found in axons that is released following white matter injury and degeneration, as well as glial fibrillary acidic protein (GFAP), which is elevated in AD.

They found that the evening-to-morning change in average plasma levels of t-tau increased following sleep loss, compared with normal sleep (p=0.0345). When the researchers examined whether sleep loss would alter overnight changes in plasma levels of Abeta, they observed no significant evening-to-morning changes in levels of Abeta-40 (p=0.24) or Abeta-42 (p=0.76) following acute sleep loss compared with sleep.

In addition, they found significant evening-to-morning decreases in Abeta-42 (-17.1 percent; p<0.0001) and GFAP in plasma (-12.1 percent; p<0.0001) regardless of sleep condition.

These findings could indicate that these proteins are controlled by a biological clock mechanismthat they exhibit so-called diurnal or circadian rhythms, Dr. Cedernaes said.

Dr. Cedernaes explained that the decrease in Abeta-42 and GFAP can provide insight into how the brain's biological clock controls either production or clearance of proteins involved in regulating the health of neurons and glial cells.

Given that other groups have found that sleep loss increases levels of Abeta-42 in the cerebrospinal fluid (CSF) of older individuals, for example, our findings may also involve changes in peripheral mechanisms that clear these proteins once they exit the central nervous system, or alternatively, our findings may represent changes that are only seen in younger, but not older individuals, he said.

There were no significant differences between the two experimental conditions in terms of how they impacted the evening-to-morning change in plasma levels of the neuroaxonal damage markers NfL (p=0.26) or GFAP (p=0.48).

One major limitation of the study was the small, homogenized sampleall were young white men in good health. Thus, the findings may not be generalizable to older people, women, or those who are already at higher risk of worse brain health due to a medical condition such as diabetes, Dr. Cedernaes said.

Future research would ideally examine whether similar changes in biomarkers for AD might occur in response to other types of sleep restriction, such as recurrent partial sleep loss, Dr. Cedernaes said, as this may provide information about how loss of sleep may promote the types of changes shown in the study.

We are also interested in establishing how these biomarkers are regulated by circadian rhythms, and whether changes are similar in individuals affected by health conditions such as obesity or type 2 diabetes, which have been found to increase the risk of dementia, he noted.

These findings should be viewed as an exploratory analysis, which needs to be confirmed in larger populations and under different settings of disrupted sleep and circadian rhythms, such as in a chronic simulation of the sleep/wake schedule that a shift worker may experience, Dr. Cedernaes wrote.

He noted that another research group using a sample of similar size also found an increase in t-tau in response to sleep loss, but they had measured the increase in subjects' CSF.

A growing number of studiesboth experimental and epidemiologicalsuggest that sleep is intertwined in the pathogenesis in AD, said Dr. Cedernaes. What is unclear at present, in humans at least, is the extent to which disrupted sleep and circadian rhythms contribute to the pathogenesis of this condition. The alternative, which research also supports, is that AD also disrupts sleep and circadian rhythms. Both of these mechanisms are often hypothesized to be at play in what we refer to as a bidirectional mechanism.

The findings are intriguing and improve our understanding of the diurnal dynamics of serum AD biomarkers, said Diego Carvalho, MD, a sleep medicine fellow at Mayo Clinic in Rochester, MN. As sleep is important for the clearance of toxic metabolic by-products and downscaling of synaptic connections, sleep loss could contribute to higher tau levels by decreased glymphatic activity and increased release of tau from greater neuronal activity with lower synaptic efficiency, he noted.

Sleep loss has also been associated with neuroinflammation, which could further contribute to tau release. Further research should assess whether serum tau could predict longitudinal tau accumulation under the condition of chronic sleep restriction.

AD researcher Barbara Bendlin, PhD, associate professor of medicine at the University of Wisconsin-Madison, noted that a growing body of literature suggests that sleep abnormalities impact the brain. Sleep abnormalities have been linked with AD pathology, and vice versa. Understanding how sleep loss impacts the brain is important because this may be a modifiable risk factor for the development of AD, she said.

She noted that several biomarkers previously assessed in the context of AD and other neurological diseases were examined, including markers related to amyloid, tau, glial activation, and neurodegeneration.

That plasma tau is elevated following a night without sleep is quite interesting; previous studies from Washington University in St. Louis have found a link between sleep and tau pathology in animal models as well as among older adults. However, more work is needed to establish whether and how elevated tau levels at younger ages may contribute to later-life neurodegenerative disease, Dr. Bendlin noted. She said that inclusion of women in a future study would improve the generalizability of the results, particularly given the increased risk of AD among women.

This small, exploratory study in 15 healthy young men is well-designed and builds on previous work looking at the effect of acute sleep loss on amyloid-beta and tau in CSF, said Brendan P. Lucey, MD, assistant professor of neurology and director of the sleep medicine section at Washington University School of Medicine.

For instance, we found that one night of sleep deprivation increases CSF Abeta by about 30 percent and tau by about 50 percent. This study suggests that plasma tau is affected by sleep deprivation whereas other proteins, such as Abeta, are not. Although these results need to be replicated, the study has implications for tracking the effect of sleep on Abeta and tau using plasma rather than CSF for screening or clinical trials. Future studies with more participants, women, and older adults are needed, he said.

Drs. Cedernaes, Carvalho, Bendlin, and Lucey had no competing interests.

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