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Objectives: We aim to investigate cognitive phenotype distribution and MRI correlates across pediatric-, elderly-, and adult-onset MS patients as a function of disease duration., Methods: In this cross-sectional study, we enrolled 1262 MS patients and 238 healthy controls, with neurological and cognitive assessments. A subset of 222 MS patients and 92 controls underwent 3T-MRI scan for brain atrophy and lesion analysis. Multinomial probabilistic models identified likelihood of belonging to cognitive phenotypes ("preserved-cognition," "mild verbal memory/semantic fluency," "mild multi-domain," "severe attention/executive," and "severe multi-domain") and experiencing MRI abnormalities based on disease duration and age at onset., Results: In all groups, the likelihood of "preserved-cognition" phenotype decreased, whereas "mild multi-domain" increased with longer disease duration. In pediatric- and adult-onset patients, the likelihood of "mild verbal memory/semantic fluency" phenotypes decreased with longer disease duration, and that of "severe multi-domain" increased with longer disease duration. Only in adult-onset patients, the likelihood of "severe executive/attention" phenotype increased with longer disease duration. All groups displayed escalating probabilities of cortical, thalamic, hippocampal, and deep gray matter atrophy over disease course. Compared to adult, pediatric-onset patients showed lower probability of experiencing thalamic atrophy with longer disease duration, while elderly-onset showed higher probability of experiencing cortical and hippocampal atrophy., Interpretation: Age at MS onset significantly influences the distribution of cognitive phenotypes and the patterns of regional gray matter atrophy throughout the disease course., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)