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Background: Cognitive interventions (CIs) in the elderly are activities that seek to improve cognitive performance and delay its deterioration. Our objectives were to study potential genetic predictors of how a CI program may influence immediate and delayed episodic verbal memory (EVM). Methods: 162 participants were elderly individuals without dementia who were randomized into parallel control and experimental groups. Participants underwent genetic testing to analyze the PICALM, ACT, NRG1, BDNF and APOE genes. We performed a broad neuropsychological assessment before and 6 months after the CI. The CI involved multifactorial training (30 sessions). The control group undertook the centre's standard activities. The main outcome measures were the genotype studied as a predictor of post-intervention changes in EVM. Results: We found the CI was associated with improvements in several cognitive functions, including immediate and delayed EVM. While no individual gene was associated with any such change, the interaction between PICALM/ACT (p = 0.008; Eta2 = 0.23) and PICALM/NRG1 (p = 0.029; Eta2 = 0.19) was associated with improved immediate EVM, and the NRG1/BDNF interaction was associated with improved delayed EVM (p = 0.009; Eta2 = 0.21). The APOEε4 genotype was not associated with any change in EVM. Conclusions: Our study shows that the participants' genotype can have an impact on the results of CIs. Cognitive stress may stimulate the interaction of various genes and as such, different types of CI should be established for distinct groups of people taking into account the individual's characteristics, like genotype, to improve the results of this type of health prevention and promotion activity. [ABSTRACT FROM AUTHOR]