Cholesterol is an important structural component of myelin and essential for brain homeostasis. Our objective was to investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS).This prospective, longitudinal study (n = 154) included 41 healthy controls, 76 relapsing-remitting MS subjects and 37 progressive MS subjects. Neurological examination, brain magnetic resonance imaging and blood samples were obtained at baseline and at 5-year follow-up visits. Cholesterol biomarkers measured included plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol and the apolipoproteins ApoA-I, Apo-II, ApoB, ApoC-II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped.Greater percentage increases in HDL-C and ApoA-I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percentage increases in low-density lipoprotein cholesterol were associated with increases in new T2 lesions. The percentage increases in HDL-C (P = 0.032) and ApoA-I (P = 0.007) were smaller in patients with relapsing-remitting MS at baseline who converted to secondary progressive MS during the 5-year follow-up period. Changes in HDL-C and ApoA-I were associated with lipoprotein lipase rs328 genotype status.Increases in HDL-C and ApoA-I have protective associations with magnetic resonance imaging measures of neurodegeneration in MS.

Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow‐up