Cognitive training, alone and combined with acetylcholinesterase inhibitors, in neurocognitive disorders: long‐term efficacy and the role of cognitive reserve on 30 months of intervention

Abstract INTRODUCTION Non‐pharmacological interventions are increasingly relevant in neurocognitive disorders (NCDs) management. Cognitive training (CT) may benefit early stages, when functional resources allow targeted stimulation. However, its long‐term effects and interaction with acetylcholinesterase inhibitors (AChEI) remain underexplored. This study aimed to investigate the 30‐month efficacy of CT, alone or combined with AChEI, in older adults with mild NCD, considering the moderating role of cognitive reserve (CR) and individual characteristics. METHODS A total of 108 individuals (mean age = 75.1 ± 6.5; 56.5% females) received either repeated CT alone ( n = 69) or CT+AChEI ( n = 39). Cognition was assessed at baseline and every 6 months using the Mini‐Mental State Examination (MMSE) and Brief Neuropsychological Examination‐2 (ENB‐2). CR was measured with the Cognitive Reserve Index questionnaire (CRIq). Linear mixed models evaluated longitudinal changes, stratified by CR and sex. RESULTS CT‐only individuals showed greater and more consistent cognitive improvements over time compared to the CT+AChEI group (MMSE: β = 0.50, 95% CI: 0.04 to 0.96, p = 0.03). Improvements were also evident in specific measures tapping executive and memory functions. Participants with lower CR benefited most from CT ( β = 0.86, 95% CI: 0.16 to 1.55, p = 0.02), while higher CR was associated with higher baseline and stability. Males showed more pronounced gains, particularly in the CT‐only group. DISCUSSION Sustained CT supports cognition in NCDs, particularly for those with lower CR. The combination with AChEI did not provide additional benefit and may reduce long‐term effectiveness, warranting further investigation. Findings emphasize the importance of tailored, long‐term approaches accounting for individual profiles. Highlights Cognitive training improved cognition over 30 months in mild NCDs. CT alone outperformed combined CT+AChEI treatment in long‐term cognitive outcomes. Individuals with lower CR benefited most from CT. Males showed greater cognitive gains, particularly in the CT‐only group. Long‐term CT efficacy supports real‐world applicability in early NCD care.