AbstractBackgroundSleep is an important physiological process, during which extracellular metabolic wastes, such as amyloid and tau protein, are cleared via paravascular pathway. Changes in the timing and structure of sleep occur across the lifespan. Increased sleep fragmentation and reductions in slow wave sleep (SWS) represent the hallmark signs of age‐related changes in sleep. The origin of sleep disturbances in AD is thought to be multifactorial. In the aging brain, the impairment of glymphatic pathway function slows the clearance of interstitial Aβ, rendering the aging brain vulnerable to neurodegenerative disease. Several authors have independently shown that glymphatic flux depends upon the expression and perivascular localization of the astroglial water channel aquaporin‐4 (AQP4).MethodIn this study, we performed and validated a mouse model of AD and chronic sleep fragmentation, a sleep disorder that mimics more correctly a real condition of intermittent and continuous awakening. We analyzed the effect of sleep fragmentation in wild type and 5xFAD mice. All the animals underwent to behavioral studies to analyze anxiety and spatial and working memory. We had validated sleep fragmentation and its effect through EEG and biomolecular analysis, by observing all the macro‐areas implied in sleep regulation.ResultWe noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to AQP4 modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects AQP4 expression according to the stage of the disease, with an up‐regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4.ConclusionNevertheless, an in‐depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms