Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein epsilon 4 allele

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 (H-1-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4. Design: A 2-year clinical and H-1-MRS follow-up cohort study. Setting: The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. Patients: We performed H-1-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. Main Outcome Measure: Levels of N-acetylaspartate as measured by H-1-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 DeltaExpanded 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.