Comprehensive investigation of sleep architecture by APOE genotype: APOE4 homozygotes have higher arousal thresholds

Abstract

Background and ObjectivesAPOE4, a genetic risk factor for Alzheimers Disease (AD), is associated with reduced functional connectivity of brain regions that regulate sleep, which may predispose persons to AD via altering sleep architecture. However, little is known about differences in sleep architecture by APOE genotype. MethodsThis cross-sectional study examined the association between APOE genotype and sleep architecture among middle-aged and older adults, using polysomnography (Sleep Heart Health Study, N=3,132). APOE genotype included: APOE4 heterozygotes, APOE4 homozygotes, APOE2 carriers, and APOE3 homozygotes. Macro sleep architecture was quantified using the percentage of time spent in rapid eye movement sleep (%REM), N1 (N1%), N2 (%N2), N3 (%N3), and arousal index. Micro sleep architecture was quantified as odds ratio product (ORP; a continuous measure of sleep depth) for overall sleep and each sleep stage, and spindle characteristics (power, density, and frequency). Linear regression was used, adjusting for covariates. ResultsThe mean age was 67, 53 percent were female, 24% were APOE4 heterozygotes, 2% were APOE4 homozygotes, 14% were APOE2 carriers, and 60% were APOE3 homozygotes. Macro sleep architecture did not vary across genotypes. Compared with APOE3 homozygotes, APOE4 homozygotes exhibited fewer arousals with age ({beta}=-0.33 per hour/year, p=0.04), resulting in significantly fewer arousals at age 70+. ORP decreased in a dose-response pattern with the number of APOE4 alleles during overall sleep and across all sleep stages (ORPAPOE3/3=0.94, ORPAPOE3/4=0.91, ORPAPOE4/4=0.87), and these group difference widened with each year of age. Finally, there was a trend for lower spindle density and power in APOE4 homozygotes relative to APOE3 homozygotes (ps=0.06). ConclusionsArousal threshold increased in a dose-response manner with each APOE4 allele, as evidenced by the findings on ORP. The differences in ORP between APOE3 homozygotes and APOE4 carriers widened further with age, paralleling age-related declines in arousal index among APOE4 homozygotes. Despite these indications of elevated arousal thresholds that might suggest less sleep fragmentation in APOE4 carriers, APOE4 homozygotes exhibited poorer sleep micro architecture, including trends toward reduced sleep spindle activity. Taken together, reduced arousability in APOE4 carriers may reflect abnormalities in cortical activation that blunt arousal rather than an indicator of healthier sleep.