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

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.