Cognitive impairment is a common feature of multiple sclerosis (MS), and its severity may be influenced by several factors, such as biological sex and levels of cognitive reserve (CR). The relationship between sex, CR, and cognition has not yet been fully investigated. Therefore, the present study aimed to explore sex differences in CR building and the effect of sex and CR on cognitive performance in MS.

233 participants underwent the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), the Stroop test, and the Cognitive Reserve Scale. The t-test was performed to compare sociodemographic variables, Italian adaptation of the Cognitive Reserve Scale, and cognitive test scores between sexes. To evaluate the effect of CR and sex and their interaction on cognitive performance several models of multivariate analyses of covariance were performed (dependent variables: all subtests of Brief Repeatable Battery of Neuropsychological Tests and Stroop scores; independent variables: sex and CR). Covariates included age, Expanded Disability Status Scale, and BDI-II scores.

Women showed higher levels of CR, particularly in daily activities (t = −5.848, p<.001), hobbies (t = −2.591, p = .010), and social life (t = −2.362, p = .011). Sex differences were noted in verbal memory and fluency (with women outperforming men) and processing speed (with men performing better than women). Multivariate analyses revealed a nonsignificant interaction between CR and sex on cognition (Λ=.950, F(10,260)=.813, p = .617, ηp2 = .050).

CR and sex seemed to affect cognitive performance independently in pwMS. This highlights the importance of considering both factors in cognitive assessment, and that both sexes may benefit from specific psychoeducational training aimed at increasing CR levels.