Spatial transcriptomics identifies regional disruptions in brain rhythmic gene expression in a mouse model of Alzheimer’s disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that impairs memory, cognitive function, and the ability to perform everyday activities. In addition to cognitive decline, behavioral disturbances in the sleep-wake cycle such as progressive fragmentation of sleep, decreased total sleep time, and increased confusion or restlessness in the evening (sundowning) are a hallmark of AD. Emerging evidence suggests that these disruptions in sleep and behavior may be underpinned by molecular dysregulation of the circadian clock. Here, we utilize Visium spatial transcriptomics to characterize diurnal transcriptional rhythms across various brain regions in APP23 transgenic mice, a model of AD, and their non-transgenic littermates in 7- and 14-month old mice. We reveal significant alterations in rhythmic gene expression in APP23-TG mice, particularly in the hippocampus and cortex. These changes were evident in 7-month-old animals, coinciding with early amyloid deposition and persisted with advancing pathology. This study offers novel insights into the large-scale dysregulation of rhythmic gene expression in AD, highlighting molecular pathways connected to circadian disruption at various stages of the disease. It underscores the potential role of these disruptions in AD progression and opens new avenues for diagnosis, treatment, and management.