Spatial transcriptomics reveals brain-wide circadian disruption in an Alzheimer’s disease model

Diurnal rhythms in brain transcription align neural, immune, and metabolic processes with the light-dark cycle and are profoundly disrupted in Alzheimer's disease (AD). However, the regional organization of diurnal transcription in the healthy and diseased brain remains poorly defined. Using large-scale spatial transcriptomics, we mapped 24-hour rhythmic transcription across cortical and subcortical regions of the mouse brain. We identified marked regional differences in rhythmicity, including distinct oscillatory signatures across cortical areas and along the rostro-caudal axis. In the APP23 mouse model of AD, pathology-vulnerable brain regions exhibited early, region-specific disruption of diurnal transcription prior to substantial amyloid plaque deposition. These findings reveal a spatially organized architecture of brain diurnal rhythms and identify early rhythmic dysregulation as a feature of Alzheimer's disease pathogenesis.