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Sleep and Alzheimer disease pathology a bidirectional relationship
Yo-El S. Ju, Brendan P. Lucey and David M. Holtzman
Abstract | Factors other than age and genetics may increase the risk of developing Alzheimer disease (AD). Accumulation of the amyloid- (A) peptide in the brain seems to initiate a cascade of key events in the pathogenesis of AD. Moreover, evidence is emerging that the sleepwake cycle directly influences levels of A in the brain. In experimental models, sleep deprivation increases the concentration of soluble A
and results in chronic accumulation of A, whereas sleep extension has the opposite effect. Furthermore, once A accumulates, increased wakefulness and altered sleep patterns develop. Individuals with early A deposition who still have normal cognitive function report sleep abnormalities, as do individuals with very mild dementia dueto AD. Thus, sleep and neurodegenerative disease may influence each other in many ways that have important implications for the diagnosis and treatment of AD.
Ju, Y.S. etal. Nat. Rev. Neurol. 10, 115119 (2014); published online 24 December 2013; http://www.nature.com/doifinder/10.1038/nrneurol.2013.269
Web End =doi:10.1038/nrneurol.2013.269
Introduction
Disturbances of sleep and circadian rhythm frequently impair the quality of life and safety of individuals with Alzheimer disease (AD). Insomnia at night, agitated behaviour in the evening and excessive sleeping during the daytime affect 2540% of patients with mild to moderate dementia due to AD in the community setting, and the intensity of these changes correlates with the severity of dementia.1 Circadian rhythms decrease in amplitude and show a phase delay, particularly in patients with advanced stages of dementia due to AD.2 Sleep problems occur very early on in the course of AD, consistent with the finding that brain regions involved in sleep and circadian control are affected early in the pathogenesis of the condition.3
Individuals with amnestic mild cognitive impairment, many of whom have very early AD,4,5 show EEG abnormalities during sleep, including fewer sleep spindles and reduced amounts of slow-wave sleep(SWS).6
The pathology of AD emerges prior to any symptoms, with the first identifiable changes
occurring ~1015years before cognitive symptoms. In the earliest stage of preclinical AD, soluble amyloid- (A) becomes insoluble and aggregates into amyloid plaques, initi ally manifesting as a reduction in soluble A42 levels in the cerebrospinal fluid (CSF).7 Our research group...