Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex.

Down syndrome is the most common genetic cause of intellectual disability and is characterized by early-onset delays in motor, cognitive, and language development. The molecular mechanisms underlying these neurodevelopmental impairments remain poorly understood. Here, we utilized single-nucleus multiomic sequencing to simultaneously profile gene expression and chromatin accessibility in the Down syndrome prefrontal cortex during early postnatal development, a critical period for synaptogenesis, neural maturation, and developmental neuroimmune interactions. Our findings reveal widespread dysregulation of chromatin accessibility and gene expression, with deficits spanning metabolic and synaptic pathways, oligodendrocyte lineage progression, and a pronounced neuroinflammatory signature. We present a molecular atlas of Down syndrome neuropathology at a critical stage of brain development, highlighting convergent neurodevelopmental and neurodegenerative pathways and informing potential targeted therapies for Down syndrome-associated neuroinflammation.