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In recent years, supported by new scientific evidence, the conceptualization of cognitive reserve (CR) has been progressively enriched and now encompasses not only cognitive stimulating activities or educational level, but also lifestyle activities, such as leisure physical activity and socialization. In this context, there is increasing interest in understanding the role of psychological factors in brain health and cognitive functioning. In a previous study, we have found that these factors mediated the relationship between CR and self-reported cognitive functioning. In this study, we have confirmed an association between two important constructs included in the psychological wellbeing and salutogenic models, “purpose in life” and “sense of coherence,” CR, as assessed using a questionnaire, and cognitive functioning, as evaluated using a comprehensive neuropsychological battery. Results from 888 middle-aged healthy participants from the Barcelona Brain Health Initiative indicate that both sense of coherence (SoC) and CR were positively associated with verbal memory, reasoning and attention, working memory, and global cognition. Moreover, the relation between CR and cognitive functioning in the different domains is partially mediated by SoC. When we controlled for brain integrity, introducing into the model neurofilament light chain measures, the mediator role of SoC was confirmed for reasoning and attention and global cognition. However, purpose in life was not associated with cognitive functioning. These results reveal the central role of the SoC construct, which mediates the association between classic CR estimates and cognitive functions …