Counteracting cognitive decline is a declared goal of regenerative medicine. Recently, partial cellular reprogramming has emerged as a promising strategy to promote tissue regeneration and restore cellular function, but whether this approach bears fruit when targeted to cell populations underlying cognitive processes remains unknown. Here, we report that partial reprogramming of engram neurons-bona fide memory trace cells-by OSK-mediated gene therapy reversed the expression of senescence- and disease-related cellular hallmarks in aged mice and models of Alzheimer's disease (AD), re-established aberrant epigenetic-transcriptional patterns pertaining to synaptic plasticity, and counteracted AD-typical neuronal hyperexcitability. Importantly, irrespective of the brain area targeted or the behavioral paradigm employed, engram reprogramming also recovered learning and memory capacities to levels of healthy young animals, suggesting cognitive rejuvenation. These results posit that partial reprogramming of specific cell populations in the brain can be exploited for cognitive restoration in aging and disease.