To investigate cognitive reserve as a possible moderator in the relationship between fatigue and depressive symptoms in persons with multiple sclerosis (PwMS). Fifty-three PwMS (37 female; mean age, 52.66; mean education, 14.81) completed comprehensive neuropsychological testing and psychosocial questionnaires assessing the perceived effects of fatigue (Fatigue Impact Scale) and depressive symptoms (Beck Depression Inventory-Fast Screen). Cognitive reserve (CR) was operationalized as Fixed CR and Malleable CR. Fixed CR was quantified as the standardized mean of years of education and a vocabulary-based estimate of premorbid intelligence. Malleable CR was quantified as the standardized mean of cognitive exertion, exercise, and socializing items from the Cognitive Health Questionnaire. Regressions on depressive symptoms examining fatigue, both conceptualizations of CR, and their interactions were explored. A Bonferroni correction was used; results were considered significant at an alpha level of p < .01. The interactions between fatigue and both conceptualizations of CR were significant, p = .005 (Fixed CR); p = .004 (Malleable CR). Simple effects tests revealed that fatigue only predicted depressive symptoms in PwMS with low Fixed CR or low Malleable CR (p’s < .001), and not in those with high Fixed or high Malleable CR (p > .01). Cognitive reserve moderated the relationship between fatigue and depressive symptoms in PwMS. Specifically, fatigue does not appear to influence depression in PwMS with high cognitive reserve. Having higher cognitive reserve (either Fixed or Malleable) may reduce the likelihood that fatigue will lead to depressive symptoms in MS.

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