An Investigation of Sleep Macro- and Microarchitecture by APOE Genotype.

OBJECTIVES: Apolipoprotein E ε4 (APOE ε4), a robust genetic risk factor for Alzheimer's disease (AD) is associated with functional connectivity deficits and amyloid pathology in brain regions involved in sleep regulation. Thus, alterations in sleep architecture may be one pathway through which ε4 contributes to Alzheimer's disease vulnerability. However, sleep architecture characteristics associated with APOE ε4 remain poorly characterized. METHODS: This cross-sectional study examined associations between APOE genotype and sleep architecture among adults aged 50-85 years enrolled in the Sleep Heart Health Study (N = 3,081). APOE genotype was classified into ε4 heterozygotes, ε4 homozygotes, ε2 carriers, and ε3 homozygotes (reference group). Sleep architecture was defined using macro-level traits (percentage of time spent in in each sleep stage and wake after sleep onset) and micro-level traits (spindle characteristics [power, density, and frequency], odds ratio product [ORP], and arousal index). Associations between APOE genotype and each sleep metric was evaluated using linear regression. RESULTS: Macroarchitecture was largely comparable across genotypes. However, substantial differences in micro-level traits were identified, including lower spindle power among ε4 homozygotes (β = -2.14, p = 0.02) and a dose-response decrease in spindle frequency at peak power with each ε4 count (βε4 heterozygotes = -0.04, p = 0.04; βε4 homozygote = -0.12, p = 0.065). Both ORP and arousal index decreased in a dose-response pattern with each ε4 count (ORP, βε4-heterozygosity = -0.03, βε4-homozygosity = -0.07, all p < 0.01; arousal index, βε4-heterozygosity = -1.02, p = 0.006, βε4-homozygosity = -1.78, p = 0.07). Between-genotype differences in ORP widened with age. Associations did not vary by sex, race, cognitive status, pTau181, or Aβ42:40 ratio. INTERPRETATION: Abnormal spindle activity observed among ε4 carriers may contribute to their elevated Alzheimer's disease risk. ε4 carriers also showed less sleep fragmentation, which may reflect diminished arousability or electroencephalogram slowing due to neurodegenerative changes. ANN NEUROL 2026 ANN NEUROL 2026.