Background: In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging.

Objective: To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4.

Methods: A 2-year clinical and (1)H-MRS follow-up cohort study. Methods: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. Methods: We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months. Methods: Levels of N-acetylaspartate as measured by (1)H-MRS.

Results: Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19).

Conclusions: The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.