Systematic Review of Environmental Factors Associated with Late-Onset Multiple Sclerosis: A Synthesis of Epidemiological Evidence

Background/Objectives: Late-onset multiple sclerosis (LOMS), characterized by an onset of disease at ≥50 years, is a distinct subset of multiple sclerosis (MS) with unique clinical and demographic features. While environmental factors such as smoking, diet, infections, and air pollution are well-studied in regard to early-onset MS, their roles in LOMS are not fully understood. This systematic review evaluates the environmental and clinical factors associated with LOMS risk to provide insights for prevention and management. Methods: A systematic review of MEDLINE, EMBASE, Web of Science, and Cochrane Library was conducted in accordance with PRISMA guidelines. Four studies (one case–control study, two cohort studies, and one cross-sectional study) investigating substance use, diet, disease-modifying therapies (DMTs), and demographic factors were included. Study quality was assessed using the Newcastle–Ottawa Scale (NOS), and findings were synthesized narratively. Results: Substance use, including smoking and the use of alcohol and drugs, was significantly associated with an increased LOMS risk (ORs 1.9–3.2). Diet quality showed no significant association with LOMS risk (HR = 1.02, 95% CI: 0.85–1.22). DMTs reduced disability progression (OR = 0.67, 95% CI: 0.55–0.81) and mortality (HR = 0.78, 95% CI: 0.65–0.94). Regional variations in symptoms were noted, with optic neuritis frequently reported as an initial symptom. Conclusions: This review identifies substance use as a significant modifiable risk factor for LOMS, while DMTs improve outcomes by reducing disability progression and mortality among elderly MS patients. The neutral findings for diet quality suggest a limited role in LOMS prevention. Further research is needed to explore broader environmental exposure and longitudinal outcomes to enhance understanding and management of LOMS.