Summary: Researchers report that disruptions to the body’s circadian rhythms can appear years before memory problems arise in Alzheimer’s disease. These early changes in sleep and activity patterns could help identify people at higher risk for the neurodegenerative disorder.
Washington University School of Medicine study finds circadian rhythm fragmentation in people with preclinical Alzheimer’s disease
People with symptomatic Alzheimer’s disease often show disturbances in their internal body clocks that affect sleep and wakefulness. New research from Washington University School of Medicine in St. Louis shows that similar circadian rhythm disruptions are present much earlier—among older adults who are still cognitively normal but show biological evidence of Alzheimer’s on brain scans or in cerebrospinal fluid.
The study’s findings, published in JAMA Neurology, suggest that monitoring daily rest–activity patterns could become a noninvasive way to identify individuals at greater risk for Alzheimer’s before cognitive symptoms begin. Early detection matters because Alzheimer’s-related brain changes can start up to 15–20 years before clinical symptoms appear.
“These participants weren’t necessarily sleep-deprived,” said first author Erik S. Musiek, MD, PhD. “Rather, their sleep was fragmented. Eight hours of consolidated night sleep has very different biological effects than eight hours scattered across short naps and wake periods.”
Complementary experiments in mice, to be published in The Journal of Experimental Medicine, demonstrate that similar circadian disruptions accelerate the accumulation of amyloid plaques in the brain—one of the hallmark pathologies of Alzheimer’s disease.
Previous Washington University work has shown that amyloid levels fluctuate across the day and night, with reductions during consolidated sleep and increases after disrupted sleep or loss of deep sleep. Building on these findings, the current human study linked fragmentation of day–night activity to preclinical indicators of Alzheimer’s.
Study design and key findings
The research team monitored circadian rhythms in 189 cognitively normal older adults (mean age 66) recruited from the Knight Alzheimer’s Disease Research Center. Participants wore actigraphy devices—similar to wrist activity trackers—for one to two weeks and completed daily sleep diaries. Some participants also underwent positron emission tomography (PET) imaging for amyloid plaques, cerebrospinal fluid testing for Alzheimer’s-related proteins, or both.
Of the 189 participants, 139 showed no evidence of amyloid pathology and generally had normal consolidated sleep/wake cycles, aside from occasional fragmentation associated with age, sleep apnea, or other factors. The remaining 50 participants had either positive amyloid PET scans or abnormal cerebrospinal fluid biomarkers. All of these individuals showed significant fragmentation of their circadian rest–activity rhythms—more daytime periods of inactivity (akin to naps) and more nighttime activity—compared with those without biomarker evidence of Alzheimer’s.
These differences persisted after statistical adjustment for age, sex, sleep apnea and other potential confounders. Measures of intradaily variability—a nonparametric marker of rest–activity fragmentation—were higher among participants with preclinical Alzheimer’s indicators, while overall rhythm amplitude was lower. In short, people with early Alzheimer’s pathology tended to have more scattered sleep and activity across 24 hours.
Mouse experiments support a causal link
In parallel animal studies, researchers disrupted circadian clock genes in a mouse model of Alzheimer’s disease. Over two months, mice with disrupted circadian rhythms developed substantially more amyloid plaques and showed altered daily patterns of amyloid levels compared with mice that maintained normal circadian rhythms. These data provide the first experimental evidence that circadian disruption can accelerate amyloid deposition in the brain.
Implications and next steps
Researchers caution that it is not yet clear whether circadian disruption is a cause of Alzheimer’s pathology or a consequence of early brain changes. Either way, circadian fragmentation appears to be detectable in the preclinical phase and may serve as a useful biomarker. The study authors plan to re-evaluate participants over time to determine whether individuals with early circadian abnormalities go on to develop cognitive decline or if the sleep and rhythm disturbances stem directly from evolving brain pathology.
Funding for the human and animal studies came from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging (NIH), with grant support including K23-NS089922, UL1-RR024992, KL2-TR000450, K08-NS079405, P01-NS074969, P01-AG03991, P01-AG026276, K01-AG053425 and P50-AG05681. Additional support was provided by an Alzheimer’s Association New Investigator Research Grant, Philips-Respironics and the Donors Cure Foundation.
Source: Washington University School of Medicine in St. Louis. Original human study published in JAMA Neurology; related animal study to appear in The Journal of Experimental Medicine. DOI for the JAMA Neurology article: 10.1001/jamaneurol.2017.4719.
Circadian Rest–Activity Pattern Changes in Aging and Preclinical Alzheimer Disease
Importance: Circadian rhythm disturbances occur in symptomatic Alzheimer disease and may contribute to disease pathogenesis, but it is unclear whether such changes appear during the presymptomatic phase.
Objective: To examine associations between circadian function, aging, and preclinical Alzheimer’s pathology in cognitively normal adults.
Design and participants: This cross-sectional study analyzed actigraphy data collected over 7–14 days from community volunteers at the Knight Alzheimer’s Disease Research Center (n=189), combined with clinical assessment, amyloid PET imaging and cerebrospinal fluid biomarker testing.
Results: Older age and male sex were associated with increased intradaily variability and reduced rhythm amplitude independent of amyloid pathology. After adjusting for age and sex, positive amyloid PET or elevated cerebrospinal fluid phosphorylated-tau/amyloid-β42 ratio correlated with greater intradaily variability, indicating fragmented rest–activity rhythms.
Conclusions: Preclinical Alzheimer’s disease is associated with fragmentation of rest–activity rhythms independent of age and sex. Aging itself also relates to circadian dysfunction, particularly in men. Circadian abnormalities in the preclinical phase suggest that disrupted rhythms could contribute to early disease processes or serve as a biomarker for preclinical Alzheimer’s.