Early-life cognitive intervention preserves brain function in aged TgF344-AD rats with sex-specific effects

Abstract

Alzheimer’s disease is characterized by progressive cognitive decline, and its effects are mitigated by cognitivereserve. We investigated whether long-term cognitive stimulation, initiated before amyloid deposition,preserves brain function in male and female TgF344-AD rats. Transgenic and wild-type (WT) rats underwentcognitive training or remained untrained. Resting-state fMRI assessed functional connectivity, the novel objectrecognition test evaluated memory, and molecular analyses examined synaptic plasticity, inhibitorysignaling, and microglial reactivity. At baseline, females showed greater task engagement and higher synapticprotein levels (PSD95, TrkB, and VGLUT) than males. Cognitive training improved connectivity and memoryin males, with limited benefits in females. At 19 months, trained transgenic rats maintained entorhinal-hippocampalconnectivity resembling WT rats, with males showing sustained plasticity markers and reducedparvalbumin-positive interneurons. Trained 11-month-old rats showed enhanced microglial recruitment toplaques and a less reactive phenotype. Overall, early and sustained cognitive stimulation enhances brain resilience,with sex-specific mechanisms shaping outcomes.