Abstract
Slow wave (or stage N3) sleep has been linked to a variety of cognitive processes. However, the role of stage N3 in the elderly is debated. The link between stage N3 and episodic memory may be weakened or changed in the older adult population, possibly due to several altered mechanisms impacting the cellular structure of the brain. The bases for the age-related dissociation between stage N3 and cognition are not understood. Since APOEε4 status is the strongest genetic risk factor for cognitive decline, we assessed whether the ε4 allele is associated with stage N3 sleep. Participants were from the population-based Osteoporotic Fractures in Men (MrOS) cohort with polysomnography and APOEε4 genotype data (n = 2,302, 100% male, mean age 76.6 years). Sleep stages were objectively measured using overnight in-home polysomnography and central electroencephalogram data were used to score stage N3 sleep. Cognitive function was assessed using the Modified Mini Mental State Exam (3MS). The APOE rs429358 single nucleotide polymorphism, which defines the APOEε4 allele, was genotyped using a custom genotyping array. Total time in stage N3 sleep was significantly higher (p<0.0001) among the 40 MrOS participants carrying two copies of the ε4 allele (62±5.2 minutes) compared with 43±1.5 minutes for carriers of one ε4 allele (n = 515) and 40±0.8 minutes for ε4 non-carriers (n = 1747). All results were independent of sleep efficiency, number of sleep cycles, and apnea hypopnea index. These findings support an association between APOEε4 genotype and sleep stage N3 in the elderly. Increased total stage N3 duration among ε4/ε4 carriers does not appear to reflect compensation for prior cognitive decline and may reflect overactive downscaling of synapses during sleep. If confirmed, these results might in part explain the high risk of age-related cognitive decline and AD among APOE ε4/ε4 carriers.
Highlights
Total stage N3 time was significantly higher among participants carrying two copies of the ε4 allele when compared to the other genotype categories in both the group with !2 point 3MS decline (p
In the present study of >2,300 older men, we confirmed a significant association between APOEε4 status and lower cognitive function scores and unexpectedly found that APOEε4 was associated with increased stage N3 duration
Average total stage N3 time was >50% longer among elderly APOE ε4/ε4 carriers when compared to those with one or no copies of the ε4 allele. While those with the APOE ε4/ε4 genotype had more stage N3 time, stage N3 was not associated with cognitive decline in MrOS [72], even after adjustment for APOEε4 statusConsistent with increased stage N3 time among ε4/ε4 genotype carriers, the APOE ε4/ε4 genotype was associated with higher sleep efficiency and decreased WASO, indicating overall less arousability
Summary
Sleep disturbances and specific sleep disorders increase with advancing age [1,2,3,4,5,6] and elevate the risk for a variety of diseases and conditions [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22] including cognitive impairment [23,24,25,26,27,28,29,30,31,32,33]. Recent research indicates that sleep may impact the cellular structure of the brain, including the ability of the brain to clear toxic metabolites that accumulate with normal neuronal function [34]. This includes beta-amyloid [34], which accumulates in apolipoprotein E (APOE) ε4 genotype carriers [35] and contributes to synaptic degeneration and cognitive decline. Given the high risk of cognitive decline and AD among APOEε4 carriers, identifying a genetic link with stage N3 sleep could advance the development of new approaches for interventions to slow the decline in cognitive function among ε4 allele carriers and that may benefit the health and wellbeing of the elderly
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