What question did this study set out to answer?

Investigate how APOE4 genotype influences sleep physiology in adolescents and its potential link to Alzheimer’s Disease risk.

May 10, 2026

0057 APOE4 Genotype and Blunted Homeostatic Sleep EEG in Young Adolescents: An Early Marker of Alzheimer’s Disease Risk?

Key Points

Investigate how APOE4 genotype influences sleep physiology in adolescents and its potential link to Alzheimer’s Disease risk.
Genotyping of 37 cognitively healthy adolescents to classify as high or low Alzheimer’s risk based on APOE4 status.
Participants underwent a 1-week sleep stabilization followed by two-night sleep measurement in the laboratory under different sleep conditions.
Analysis of NREM delta power across sleep cycles using a linear mixed-effects model, controlling for age and sex.
Main effects of sleep cycle and condition confirmed (delta decreased across cycles, increased after wake-extension; p<.001).
Significant interaction indicated high-risk youth showed a blunted decay in NREM delta power after wake-extension compared to baseline (b=.043; p<.001).
No difference in delta decay noted for low-risk group across conditions (b=.01; p=.19).

Abstract

Abstract Introduction The e4 allele of the Apolipoprotein (APOE4) contributes to sleep disturbances and increases risk for Alzheimer’s Disease (AD). When in life these risks emerge is unknown. Specifically, whether APOE4 status alters sleep in adolescents has not been investigated. We present a study of sleep physiology under rested and homeostatic challenged conditions in healthy adolescents whose genetic risk for AD is heightened by APOE4 carrier status. Methods Thirty-seven cognitively healthy youth (9.6-15.8 12.2±1.5 years; 18M) were genotyped as high (n=11; 9.6-13.1 11.6±1.3 years; 3M) or low (n=26, 9.6-15.8 12.4±1.6 years; 15M) risk for AD (APOE4 carrier ≥1 allele vs. non-carrier 0 alleles). After 1-week of 9.5h sleep stabilization and a laboratory adaptation night, participants slept in the laboratory for two consecutive nights: baseline (9.5h TIB) followed by wake-extension (4.5h delayed bedtime; 5h TIB). PSG included 9 EEGs (F3,Fz,F4,C3,Cz,C4,P3,P4,O1,O2). After staging (R random intercepts: subject, EEG-channel) examined gene-risk (high vs. low), sleep condition (baseline vs. wake-extension) and NREM cycle . Results We identified expected main-effects of cycle (i.e., delta decayed over time; F(2,1804.8)=672.1; p.001) and condition (i.e., delta increased after wake-extension (F(1,1808.3)=118.6; p.001). However, we detected a significant interaction of gene-risk, sleep condition, and NREM cycle (F(2,1804.3)=3.3, p=.039); i.e., the time-course of delta power was moderated by gene-risk. Wake extension for high-risk youth showed a blunted decay of delta between cycles 1 and 2 (b=.043; p.001) relative to baseline; this effect was not found for the low-risk group (b=.01; p=.19) where delta decay did not differ between sleep conditions. Conclusion These data indicate that genetic risk of Alzheimer’s Disease may affect the homeostatic response of NREM delta power in healthy youth. Whether these differences, when coupled with the routine experience of adolescent insufficient sleep, contribute to lifelong risk (e.g., altered glymphatic clearance or amyloid-beta accumulation) remains unknown. Our findings offer novel evidence of a sleep signature for dementia risk decades before cognitive decline, opening unprecedented opportunities for prevention. Support (if any) P20GM103645 (Project Leader:JMS); Zimmerman Innovation Award (JMS, MAC); P20GM139743 (PI:MAC)

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