Background
•Sleep disturbance and the apolipoprotein E (APOE) ε4 allele are established risk factors for Alzheimer’s disease (AD).1,2
•Regular physical activity (PA) may mitigate sleep disturbance, particularly during midlife (40-65 years),3 an important life stage for lifestyle changes to lower AD risk.
•However, it remains unclear whether the relationship between PA and sleep differs by genetic risk in this age group or across sleep quality domains.
•We investigated the effects of a 12-month PA intervention on subjective sleep quality as a function of APOE-ε4 carriage in cognitively unimpaired (MoCA ≥26) middle-aged adults with a family history of AD (FH+).
Methods
•Middle-aged adults (N=171, 56.3±6.3 yrs, 86% female) were randomized to an exercise or usual-care control group for 12 months (NCT03876314; NIHR01AG058919).4
•Exercise consisted of virtual aerobic and resistance training 3 days/week; control participants received monthly educational materials.
•APOE-ε4 carriage was determined from saliva (70 carriers, 96 non-carriers).
•Sleep quality, duration, and daytime dysfunction were assessed via the Pittsburgh Sleep Quality Index (PSQI) at pre- and post-test.
•Higher PSQI scores reflect worse sleep quality and greater daytime dysfunction.
•Longitudinal mixed-effects models with random intercepts estimated Time*Group*APOE-ε4 interactions under maximum likelihood estimation.
Baseline Results
•APOE-ε4 carriers reported 26 more minutes of sleep than non-carriers (p=.006).
•No exercise vs control between group differences in covariates (age, BMI, sex, APOE-ε4 carriage) or sleep-related outcome variables (all p>.05).
Longitudinal Results
•Intervention adherence varied by cohort (cohort 1: 61%; cohort 2: 58%; cohorts 3-11: 74%).
•Variation may be explained by impacts of COVID-19 (see Etnier, Armstrong, et al.’s poster)
•Significant Time*Group (p=.002) and Time*Group*APOE-ε4 (p=.040) interactions were observed for subjective daytime dysfunction.
•From pre- to post-test, APOE-ε4 non-carriers in the exercise group reported improvements in subjective daytime dysfunction (Δ=0.626, d=0.77, p=.0007).
•No significant Time*Group or Time*Group*APOE-ε4 interactions were observed for other outcome variables (all p>.05).
Discussion
•In this predominately female sample of middle-aged adults with a FH+, 12-months of exercise improved subjective daytime dysfunction in APOE-ε4 non-carriers, but not in controls or carriers.
•Only daytime dysfunction improved, albeit in APOE-ε4 non-carriers only, suggesting exercise may enhance daytime functioning even in the absence of changes to overall sleep quality or duration.
•APOE-ε4 carriage may moderate sleep-related benefits of PA, likely through APOE-ε4-related neuroinflammation,5 potentially reflecting a higher threshold for exercise-induced improvements among APOE-ε4 carriers.
•Given the subjective nature of the PSQI, replication leveraging objective sleep quality measures (e.g., polysomnography) are necessary and the predominantly female sample prohibits generalization to broader samples.
•More targeted lifestyle interventions (e.g., greater exercise dose) may be needed to improve sleep-related daytime functioning in those at elevated genetic risk for AD.
References
1.Bubu et al. Sleep, Cognitive impairment, and Alzheimer’s disease: A Systematic Review and Meta-Analysis. Sleep. 2017.
2.Duara et al. Alzheimer’s disease: interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age of onset. Neurology. 1996.
3.Gao et al. Effects of different types of exercise on sleep quality based on Pittsburgh Sleep Quality Index in middle-aged and older adults: a network meta-analysis. J Clin Sleep Med. 2024.
4.Park et al. The effect of physical activity on cognition relative to APOE genotype (PAAD-2): study protocol for a phase II randomized control trial. BMC Neurol. 2020.
5.Huang et al. Sleep quality, APOE ε4, and Alzheimer’s disease. BMC Med. 2025.
Research reported in this presentation was supported by the National Institute On Aging of the National Institutes of Health under Award Number R01AG058919. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
