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

Alzheimer's disease is characterized by progressive cognitive decline, and its effects are mitigated by cognitive reserve. 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 underwent cognitive training or remained untrained. Resting-state fMRI assessed functional connectivity, the novel object recognition test evaluated memory, and molecular analyses examined synaptic plasticity, inhibitory signaling, and microglial reactivity. At baseline, females showed greater task engagement and higher synaptic protein levels (PSD95, TrkB, and VGLUT) than males. Cognitive training improved connectivity and memory in males, with limited benefits in females. At 19 months, trained transgenic rats maintained entorhinal-hippocampal connectivity resembling WT rats, with males showing sustained plasticity markers and reduced parvalbumin-positive interneurons. Trained 11-month-old rats showed enhanced microglial recruitment to plaques and a less reactive phenotype. Overall, early and sustained cognitive stimulation enhances brain resilience, with sex-specific mechanisms shaping outcomes.