Unraveling cholesterol metabolism in multiple sclerosis: Gender-specific patterns and predictive biomarkers

Multiple Sclerosis (MS) is a chronic, immune-mediated disease characterized by demyelination, axonal damage, and cognitive impairment. Emerging evidence suggests that disruptions in cholesterol metabolism contribute to MS progression, as cholesterol and related sterols play a crucial role in immune regulation and myelin composition. This study analyzed cholesterol, non cholesterol sterols (NCS), and oxysterols in serum and cerebrospinal fluid (CSF) from 127 individuals with clinically isolated syndrome, relapsing-remitting MS or primary progressive MS as well as 49 individuals wirh other neurological disorders (OND). Additionally, serum Neurofilament light chain (NfL), a marker of axonal damage, was measured. Results revealed significant alterations in cholesterol metabolism in MS. Serum cholesterol and cholesterol synthesis markers were elevated, while CSF cholesterol levels were reduced, indicating a contrasting pattern between peripheral and central cholesterol metabolism. Cholesterol absorption was notably decreased in individuals with MS. NfL levels mirrored the pattern observed in serum cholesterol but were inversely related to CSF cholesterol, suggesting a potential link between axonal damage and disease progression. Importantly, serumCSF correlation varied by MS type and gender. The observed gender-specific differences in cholesterol metabolism may contribute to our understanding of the distinct disease manifestations in men and women and should be taken into account in both the diagnosis and treatment of MS. The findings also suggest that impaired cholesterol synthesis in the brain may play a role in MS pathology, with reduced CSF cholesterol levels potentially serving as a marker of demyelination. Furthermore, specific serum (oxy)sterols emerged as promising biomarkers for MS diagnosis and progression. Together, these insights improve our understanding of MS and may support the identification of novel diagnostic markers and therapeutic targets.