Body Clock Disruptions Occur Years Before Memory Loss in Alzheimer’s

Summary: According to researchers, circadian disruptions can occur years before symptoms of Alzheimer’s develop. The findings could help to identify those at risk of developing the neurodegenerative disease as they age.

Source: UWSTL.

People with Alzheimer’s disease are known to have disturbances in their internal body clocks that affect the sleep/wake cycle and may increase risk of developing the disorder. Now, new research at Washington University School of Medicine in St. Louis indicates that such circadian rhythm disruptions also occur much earlier in people whose memories are intact but whose brain scans show early, preclinical evidence of Alzheimer’s.

The findings potentially could help doctors identify people at risk of Alzheimer’s earlier than currently is possible. That’s important because Alzheimer’s damage can take root in the brain 15 to 20 years before clinical symptoms appear.

The research is published Jan. 29 in the journal JAMA Neurology.

“It wasn’t that the people in the study were sleep-deprived,” said first author Erik S. Musiek, MD, PhD, an assistant professor of neurology. “But their sleep tended to be fragmented. Sleeping for eight hours at night is very different from getting eight hours of sleep in one-hour increments during daytime naps.”

The researchers also conducted a separate study in mice, to be published Jan. 30 in The Journal of Experimental Medicine, showing that similar circadian disruptions accelerate the development of amyloid plaques in the brain, which are linked to Alzheimer’s.

Previous studies at Washington University, conducted in people and in animals, have found that levels of amyloid fluctuate in predictable ways during the day and night. Amyloid levels decrease during sleep, and several studies have shown that levels increase when sleep is disrupted or when people don’t get enough deep sleep, according to research by senior author, Yo-El Ju, MD.

“In this new study, we found that people with preclinical Alzheimer’s disease had more fragmentation in their circadian activity patterns, with more periods of inactivity or sleep during the day and more periods of activity at night,” said Ju, an assistant professor of neurology.

The researchers tracked circadian rhythms in 189 cognitively normal, older adults with an average age of 66. Some had positron emission tomography (PET) scans to look for Alzheimer’s-related amyloid plaques in their brains. Others had their cerebrospinal fluid tested for Alzheimer’s-related proteins. And some had both scans and spinal fluid testing.

Of the participants, 139 had no evidence of the amyloid protein that signifies preclinical Alzheimer’s. Most had normal sleep/wake cycles, although several had circadian disruptions that were linked to advanced age, sleep apnea or other causes.

But among the other 50 subjects — who either had abnormal brain scans or abnormal cerebrospinal fluid — all experienced significant disruptions in their internal body clocks, determined by how much rest they got at night and how active they were during the day. Disruptions in the sleep/wake cycle remained even after the researchers statistically controlled for sleep apnea, age and other factors.

The study subjects, from Washington University’s Knight Alzheimer’s Disease Research Center, all wore devices similar to exercise trackers for one to two weeks. Each also completed a detailed sleep diary every morning.

By tracking activity during the day and night, the researchers could tell how scattered rest and activity were throughout 24-hour periods. Subjects who experienced short spurts of activity and rest during the day and night were more likely to have evidence of amyloid buildup in their brains.

These findings in people reinforce the mouse research from Musiek’s lab. In that study, working with first author Geraldine J. Kress, PhD, an assistant professor of neurology, Musiek studied circadian rhythm disruptions in a mouse model of Alzheimer’s. To disrupt the animals’ circadian rhythms, his team disabled genes that control the circadian clock.

alzheimer's brain
By tracking activity during the day and night, the researchers could tell how scattered rest and activity were throughout 24-hour periods. Subjects who experienced short spurts of activity and rest during the day and night were more likely to have evidence of amyloid buildup in their brains. image is in the public domain.

“Over two months, mice with disrupted circadian rhythms developed considerably more amyloid plaques than mice with normal rhythms,” Musiek said. “The mice also had changes in the normal, daily rhythms of amyloid protein in the brain. It’s the first data demonstrating that the disruption of circadian rhythms could be accelerating the deposition of plaques.”

Both Musiek and Ju said it’s too early to answer the chicken-and-egg question of whether disrupted circadian rhythms put people at risk for Alzheimer’s disease or whether Alzheimer’s-related changes in the brain disrupt circadian rhythms.

“At the very least, these disruptions in circadian rhythms may serve as a biomarker for preclinical disease,” said Ju. “We want to bring back these subjects in the future to learn more about whether their sleep and circadian rhythm problems lead to increased Alzheimer’s risk or whether the Alzheimer’s disease brain changes cause sleep/wake cycle and circadian problems.”

About this neuroscience research article

Funding: This work was supported by the National Institute of Neurological Disorders and Stroke and the National Institute on Aging of the National Institutes of Health (NIH), grant numbers K23-NS089922, UL1-RR024992, KL2-TR000450, K08-NS079405, P01-NS074969m P01-AG03991, P01-AG026276, K01-AG053425 and P50-AG05681. Additional funding from an Alzheimer’s Association New Investigator Research Grant, Philips-Respironics and the Donors Cure Foundation.

Source: Jim Dryden – UWSTL
Publisher: Organized by
Image Source: image is in the public domain.
Original Research: Abstract in JAMA Neurology.

Second study will appear in Journal of Experimental Medicine during the week of January 29 2018.

Cite This Article

[cbtabs][cbtab title=”MLA”]UWSTL “Body Clock Disruptions Occur Years Before Memory Loss in Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 29 January 2018.
<>.[/cbtab][cbtab title=”APA”]UWSTL (2018, January 29). Body Clock Disruptions Occur Years Before Memory Loss in Alzheimer’s. NeuroscienceNews. Retrieved January 29, 2018 from[/cbtab][cbtab title=”Chicago”]UWSTL “Body Clock Disruptions Occur Years Before Memory Loss in Alzheimer’s.” (accessed January 29, 2018).[/cbtab][/cbtabs]


Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease

Importance Circadian rhythm disturbances occur in symptomatic Alzheimer disease (AD) and have been hypothesized to contribute to disease pathogenesis. However, it is unknown whether circadian changes occur during the presymptomatic phase of the disease.

Objective To examine the associations between circadian function, aging, and preclinical AD pathology in cognitively normal adults.

Design, Setting, and Participants This cross-sectional study was conducted using community volunteers from the Knight Alzheimer’s Disease Research Center at Washington University in St Louis. Cognitively normal participants (n = 205) underwent 7 to 14 days of actigraphy in their home environment between 2010 and 2012, in addition to clinical assessment, amyloid imaging with Pittsburgh Compound B (PiB), and cerebrospinal fluid biomarker collection. Data collected from 3 years before to 6 months after actigraphy were included. Sixteen participants were excluded owing to incomplete data collection.

Main Outcomes and Measures Circadian rhythm analysis was performed on actigraphy data using 3 methods: cosinor, nonparametric, and empirical mode decomposition. Preclinical AD was assessed by longitudinal clinical assessment, amyloid imaging with PiB, and cerebrospinal fluid biomarker collection.

Data from 189 participants were included in the analyses. The mean (SD) age was 66.6 (8.3) years, and 121 participants (64%) were women. Older age (β = .247; P = .003) and male sex (β = .170; P = .04), in the absence of amyloid pathology, were associated with a significant increase in intradaily variability, a nonparametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. After correction for age and sex, the presence of preclinical amyloid plaque pathology, assessed by positive PiB imaging (mean [SD], 0.804 [0.187] for PiB negative vs 0.875 [0.178] for PiB positive; P = .05) or increasing cerebrospinal fluid phosphorylated-tau to amyloid β 42 ratio (β = .231; P = .008), was associated with increased intradaily variability, indicating rest-activity rhythm fragmentation.

Conclusions and Relevance
Preclinical AD is associated with rest-activity rhythm fragmentation, independent of age or sex. Aging was also associated with circadian dysfunction independently of preclinical AD pathology, particularly in men. The presence of circadian rhythm abnormalities in the preclinical phase of AD suggests that circadian dysfunction could contribute to early disease pathogenesis or serve as a biomarker of preclinical disease.

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