ORAL ADMINISTRATION OF DUAL OREXIN RECEPTOR ANTAGONISTS (DORAS) IMPROVES DIMINISHED DELTA AND MAY PROMOTE EFFICIENT BRAIN WASTE CLEARANCE IN YOUNG 3XTG-AD MICE

Alzheimer’s Disease (AD) is characterized by cognitive decline and aggressive pathology. Many with AD also have impaired sleep (Mander et al., 2016). Recently, it was found that extracellular waste is cleared by the coordinated effects of cerebrospinal fluid and astrocytes of the perivascular space, which is thought to be optimized by the slow oscillations (i.e. delta) generated during slow wave sleep (SWS; Xie et al., 2013) and potentially micro-arousals (Haugland et al., 2025). We aim to use an early marker for sleep dysfunction to treat early sleep deficits and facilitate natural clearance by targeting the orexin pathway, a sleep/wake cycle regulator. Previously, we reported spatial learning and memory and sleep impairments prior to plaque formation in 6-month-old female 3xTg-AD mice (Stimmell et al., 2019; Cushing et al., 2020). Here we show that sleep is fragmented in older 9-month-old mice. While sleep is not fragmented at earlier timepoints, prior to cognitive impairments, delta power (0.5-4Hz) is reduced compared to healthy controls in 3xTg-AD mice and TgF344-AD rats. Further, a 50-minute rest session is sufficient for identifying reduced delta. We are currently administering a dual orexin receptor antagonist (DORA) to restore healthy sleep in AD rodent models. Administration of suvorexant (a DORA) significantly increased total delta power and power spectral density over the first six hours of the inactive phase. This suggests the potential to identify an ideal early treatment timepoint to restore sleep. We are investigating the impacts of DORA administration to prevent impaired cognition at later timepoints.