Using single-nucleus RNA sequencing, researchers detailed cell-specific molecular responses to exercise in the hippocampal dentate gyrus of an Alzheimer’s disease mouse model. Exercise restored subsets of dysregulated genes primarily in immature neurons, and modulated disease-associated microglia and neurovascular astrocytes. Oligodendrocyte progenitor cells showed significant gene expression recovery. Validation with human Alzheimer’s data highlights molecular mediators by which physical activity confers neuroprotection and may inform therapeutic approaches targeting specific cell types to mitigate neurodegenerative progression.