7 September 2012. Circadian rhythms are off in Alzheimer's disease (AD), illustrated in part by "sundowning," in which patients get confused and agitated late in the day and into the night. Could Aβ have anything to do with those changes in diurnal rhythms? Possibly, according to a paper in the September 5 Science Translational Medicine. Aβ deposits disrupt normal Aβ fluctuations in mice and disturb the animals' sleep patterns. People who test positive for brain amyloid lose normal Aβ rhythms as well. Alzforum reported on these findings from the Alzheimer's Association International Conference held in Vancouver last July (see ARF related news story).
Scientists led by David Holtzman at Washington University School of Medicine, St. Louis, Missouri, found that in APP/PS1 transgenic mice, Aβ in the brain’s interstitial fluid fluctuated with a normal circadian rhythm right up until brain plaques developed. Then the daily oscillations diminished and sleep rhythms careened off course. Actively immunizing young mice against Aβ42 prevented both plaque accumulation and any circadian or sleep changes.
Could these findings be relevant to humans? First author Jee Hoon Roh and colleagues determined that cerebrospinal fluid Aβ rhythms deteriorated in plaque-positive young adults who carry a presenilin mutation. The scientists have not yet investigated sleep disturbances in this cohort, but will in the future, Roh said.
"The study adds support to an emerging area of investigation in neurodegeneration—the role of sleep-wake disturbances in altering the progression of these disorders," wrote Allan Pack and colleagues at the University of Pennsylvania, Philadelphia, in an accompanying editorial. "The results suggest that monitoring sleep-wake disturbances ... could provide a noninvasive indicator of early AD," they wrote, adding that researchers need to do more work in rodents and humans to confirm the hypothesis.—Gwyneth Dickey Zakaib.
Roh JH, Huang Y, Bero AW, Kasten T, Stewart FR, Bateman RJ, Holtzman DM. Disruption of the sleep wake cycle and diurnal fluctuation of amyloid-β in mice with Alzheimer’s disease pathology. Sci Transl Med 2012 Sept 5; 4(150):150ra122. Abstract
Gerstner JR, Perron IJ, Pack AI. The Nexus of Aβ, Aging, and Sleep. Sci Trans Med 2012 Sept 5; 4(150):150fs34. Abstract