A large body of evidence demonstrates that sleep disturbance increases the risk for Alzheimer disease (AD).1-3 A recent meta-analysis of 27 observational studies1 determined that individuals with sleep problems had a 1.68 times higher risk for developing cognitive impairment or AD and that 15% of AD prevalence may be directly attributable to sleep dysfunction. Recent advances have focused on potential mechanisms driving sleep disturbance as a risk factor in preclinical AD. In cognitively healthy older adults, self-reports of worse sleep quality and daytime sleepiness were associated with β-amyloid (Aβ) and tau accumulation, as indicated by cerebrospinal fluid measures.4 Other studies5,6 show an effect of Aβ on non–rapid eye movement (NREM) sleep physiology, with high levels of Aβ correlating with deficient slow wave activity and impaired performance on a sleep-dependent memory task. Increasing evidence indicates that these associations linking sleep disruption and the pathophysiologic features of AD may be bidirectional.2 Rodent models of AD show greater sleep fragmentation and shorter amounts of NREM and rapid eye movement sleep.7 In an experimental manipulation of NREM sleep in healthy, middle-aged participants,8 greater slow wave activity suppression led to greater cerebrospinal fluid Aβ levels the subsequent morning. Moreover, rodent studies indicate that wakefulness results in the accumulation of Aβ,9 whereas NREM sleep supports the glymphatic clearance of Aβ peptides.10 Despite this evidence, the established link between poor sleep quality and the risk for cognitive decline and AD has not yet been demonstrably linked to a longitudinal mechanism in humans. Although these prior studies outline cross-sectional links between sleep and biomarkers of AD, as well as a potential mechanism that associated sleep with AD pathology on a short timescale,8 how chronic sleep disturbance may facilitate increased AD pathophysiologic progression during a timescale of years remains unresolved. This is a critical knowledge gap because long-term accumulation of Aβ and tau ultimately leads to the development of AD.
Winer JR, Mander BA. Waking Up to the Importance of Sleep in the Pathogenesis of Alzheimer Disease. JAMA Neurol. 2018;75(6):654–656. doi:10.1001/jamaneurol.2018.0005
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