0083 APOE4 Exacerbates Amyloid-Related Sleep Impairments

Abstract Introduction Apolipoprotein E ε4 (E4) is the most potent genetic risk factor for Alzheimer's disease (AD), present in up to 60% of AD patients. Concurrently, sleep impairment is a causal contributor to AD pathogenesis, initiating a vicious, bidirectional feedback loop with β-amyloid (Aβ) pathology that E4 appears to amplify. E4 carriers face elevated risk of amyloid-related imaging abnormalities (ARIA) during Aβ-clearing therapies, underscoring an urgent need for E4-specific, ARIA-sparing therapeutic strategies. We hypothesized that E4 exacerbates amyloid-induced sleep impairments by synergizing with oligomeric Aβ species and driving premature circuit dysfunction. Methods We crossed APPswe/PS1dE9 (APP) transgenic mice with human APOE knock-in mice, establishing E3/APP and E4/APP experimental lines. Sleep microarchitecture, specifically cortical slow oscillation (SO, < 1 Hz) power and propagation, was assessed using in vivo widefield voltage-sensitive dye (VSD) imaging under anesthesia. Sleep macroarchitecture, specifically sleep stage duration and fragmentation, was monitored in non-anesthetized, freely-moving mice using wireless, fully implantable EEG/EMG telemetry. The effect of CN-105, an APOE-mimetic peptide, on sleep and SO was examined. Results E4/APP mice exhibited profound sleep deficits compared to E3/APP controls at 2 months of age, prior to significant plaque deposition. VSD imaging revealed that E4/APP mice exhibited reduced SO power and impaired intra- and interhemispheric functional connectivity. This 2-month onset is dramatically accelerated, as APP mice lacking human APOE did not show SO impairments until 3 months, and E4-only mice were unimpaired at 2 months. Telemetry recordings showed that 2-month-old E4/APP mice displayed significantly reduced NREM sleep, increased wakefulness, and greater sleep fragmentation compared to E3/APP counterparts. Acute 1.5-day treatment with CN-105 rescued micro- and macroarchitectural deficits, restoring SO power and increasing NREM sleep duration in E4/APP mice. Conclusion The E4 genotype functions as an active and reversible driver of sleep impairment, synergizing with oligomeric Aβ species to accelerate the collapse of sleep-regulating neural circuits. The acute rescue of these deficits with CN-105 demonstrates that this E4-driven circuit dysfunction is an active, ongoing process and not yet a permanent structural failure. These findings validate sleep as an important modifiable risk factor in E4 carriers, offering a promising disease-modifying strategy. Support (if any) Cure Alzheimer’s Fund