Abstract Introduction APOE4, a genetic risk factor for Alzheimer’s Disease (AD), is associated with reduced functional connectivity of brain regions that regulate sleep, predisposing persons to AD via altering sleep architecture. However, sleep architecture profiles associated with APOE4 genotype remain unknown. Methods This study examined the association between APOE genotype and sleep architecture among middle-aged and older adults, using in-home polysomnography (Sleep Heart Health Study, N=3,132). APOE genotype included: APOE4 heterozygotes, APOE4 homozygotes, APOE2 carriers (homozygotes and heterozygotes), and APOE3 homozygotes. Macro sleep architecture was quantified using the percentage of time spent in rapid eye movement sleep, N1, N2, N3, and arousal index. Micro sleep architecture was quantified as odds ratio product (ORP; a continuous measure of arousal likelihood) for overall sleep and each sleep stage, and spindle characteristics (power, density, and frequency). Linear regression was used, adjusting for covariates. Results Mean age was 67, 53% were female, 24% were APOE4 heterozygotes, and 2% were APOE4 homozygotes. Macro sleep architecture did not vary across genotypes. Compared with APOE3 homozygotes, APOE4 homozygotes exhibited fewer arousals with age (β=-0.33 per hour/year, p=0.04), resulting in significantly fewer arousals at age 55+. 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). The difference in ORP 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). Conclusion APOE4 carriers -particularly APOE4 homozygotes- exhibit elevated arousal thresholds and worse sleep microarchitecture compared to APOE3 homozygotes. Elevated arousal thresholds are reflected in the dose-response decline in ORP with each APOE4 allele and in the additional yearly decrease in ORP observed among carriers, consistent with age related declines in arousal index. Worse sleep microarchitecture is suggested by trends toward reduced sleep spindle activity among APOE4 homozygotes. Nonetheless, sleep macroarchitecture remained comparable across APOE genotypes. Taken together, reduced arousability in APOE4 carriers may reflect abnormalities in cortical activation leading to an arousal rather than a sign of healthier sleep. Support (if any) This work was supported by the National Institute of Health (P30AG021342) and the Alzheimer’s Association (AARFD-24-1306796).
Cho et al. (Fri,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: