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Abstract This study explored the efficacy of a new rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to two aetiologies: prodromal to Alzheimer’s dementia or consequent to Parkinson’s disease. We investigated whether this tool could improve cognitive performances, with effects at least similar to programs used in clinical practice. Leveraging studies suggesting a neuromodulatory effect of PA, we explored if the PA+SGs combined treatment could influence plasticity-related mechanisms assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). 23 MCI patients were randomized into three intervention groups: PA+SGs, SG-only, and SCR, completing 10 treatment sessions. Before and after the treatment, patients underwent neuropsychological assessment and blood sampling acquisition. At baseline, all groups showed similar demographic, clinical, and biological characteristics. Post-treatment, the PA+SGs group improved in memory, executive function, and visuospatial abilities, although these changes were not statistically different from the control groups. Increased BDNF serum levels were observed only in the PA+SG group and were positively correlated with improved memory and language performance. Our findings suggest that combining PA with cognitive training may improve cognitive functioning in MCI patients, with results similar to SCR. Further, PA seems to enhance neuroplasticity mechanisms that may support the behavioral improvements of cognitive training. Future research should confirm these findings and delve deeper into the relationship between cognitive impairment and its rehabilitation, based also on the underlying neurobiological mechanisms. Trial registration number(Clinicaltrials.gov): NCT05826626
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