Genetic Predisposition or Environmental Accumulation? Investigating Late-Onset Multiple Sclerosis

Late-onset multiple sclerosis (LOMS), often defined as symptom onset at or after age 50, is associated with a more aggressive disease course compared to the most common adult-onset MS (AOMS). However, its biological and clinical characteristics remain underexplored. There is also lack of consistent definition for individuals with onset between ages 40-49, raising questions as to which group it should be included in. Our aim was to characterize the clinical, genetic, and environmental features of LOMS and assess whether the ≥50 years cutoff best defines this subgroup. We analyzed clinical, demographic, genetic, and environmental data from 10,545 individuals in the Swedish MS registry. Disease severity was assessed using Multiple Sclerosis Severity Scores, Expanded Disability Severity Score milestones, and progression to secondary progressive MS. Key HLA alleles, severity-associated SNPs, and genetic risk scores were evaluated, as well as environmental exposures including smoking, sun exposure, BMI, education, and EBV serostatus. Individuals with LOMS showed more rapid disease progression, greater disability, and lower treatment exposure compared to younger onset groups. Genetic risk variants had a limited impact on LOMS susceptibility; while smoking and low sun exposure were consistently associated with increased disease severity and risk, even after adjusting for birth-year and covariates. Higher educational attainment was protective against both disease severity and LOMS. Individuals with onset between 40-49 years (IOMS) exhibited intermediate clinical and biological features. These findings support age-at-onset ≥50 years as the most appropriate definition for LOMS. The results highlight the dominant role of lifelong environmental exposures over genetic burden in influencing MS trajectory in older adults.