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From the Departments of Neurology (Drs. Chapman, Achiron, and Korczyn), Physiology and Pharmacology (Drs. Chapman, Vinokurov, and Korczyn), and Biochemistry (Dr. Chapman), Sackler Faculty of Medicine; Department of Neurology and Neuroimmunology Clinic (Drs. Chapman, Birnbaum, and Korczyn), Tel Aviv Medical Center; Neuroimmunology Unit (Dr. Achiron), Sheba Medical Center; Department of Neurobiochemistry and Life Sciences (Dr. Michaelson), Tel Aviv University; Department of Neurology (Dr. Karussis), Hadassah Medical Center, Jerusalem, Israel; and Teaching Department of Neurology (Dr. Mitosek–Szewczyk), School of Medicine, Lublin, Poland.
Address correspondence and reprint requests to Dr. A.D. Korczyn, Sierazki Chair of Neurology, Tel Aviv University, Israel; e-mail: neuro13{at}ccsg.tau.ac.il
BACKGROUND AND OBJECTIVE: The authors recently reported that the APOE 
4 allele is associated with significantly greater progression of disability in a 2-year follow-up of patients with MS. In this study, these findings are substantiated and extended in a much larger group of patients followed for up to 40 years.
METHODS: Two hundred five patients with clinically definite MS who were genotyped for the APOE 4 carrier state were included. Groups of patients with (n = 41) and without (n = 164) APOE 4 alleles were compared for latency to expanded disability status scale (EDSS) scores of 4.0 and 6.0 by Kaplan–Meier analysis with the log rank test. The results were adjusted for age at onset and sex by Cox regression analysis.
RESULTS: The APOE 4 allele frequency in patients with MS (0.10) was similar to that in the general Israeli population. There was a significant effect of APOE genotype on the latency to reach EDSS 4.0 and 6.0 (p = 0.0002 and p = 0.0006 by two-tailed log rank test). Median latencies were shorter by 12 and 11 years in the APOE 4 group for these outcomes. These results were significant after adjustment for age at onset and sex.
CONCLUSIONS: The APOE 4 allele is associated with significantly faster progression of disability in MS. This is the first genetic factor to be identified with a major impact on the progression of disability in this disease.
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