APOE genotype is a major predictor of long-term progression of disability in MS

Department of Neurology, Sackler Faculty of Medicine, Tel Aviv Medical Center, Israel.
Neurology (Impact Factor: 8.3). 03/2001; 56(3):312-6. DOI: 10.1212/WNL.56.3.312
Source: PubMed

ABSTRACT The authors recently reported that the APOE epsilon4 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.
Two hundred five patients with clinically definite MS who were genotyped for the APOE epsilon4 carrier state were included. Groups of patients with (n = 41) and without (n = 164) APOE epsilon4 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.
The APOE epsilon4 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 epsilon4 group for these outcomes. These results were significant after adjustment for age at onset and sex.
The APOE epsilon4 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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    • "The study from Sardinia showed that the APOE-ε4 allele increases the risk of PPMS, but only in women [27] whereas the study from The Netherlands did not confirm any such association [44]. A recent study revealed that African Americans female MS patients with APOE-ε4 had an earlier age of onset than Caucasian female MS patients [45], also Albeit Chapman et al. found an earlier age of onset in the APOE- ε4 carriers [26]. Most of other studies as well failed to find such positive association [29–31,33,35,37–39,41]. "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system. Evidences linking apolipoprotein E (APOE) to myelin repair, neuronal plasticity, and cerebral inflammatory processes suggest that it may be relevant in MS. The main goal of this study was to determine whether the APOE genotypes and alleles are associated with MS patients. In total, 147 MS cases and 168 control subjects from Iranian population were genotyped for APOE gene using PCR-RFLP method. The frequency of APOE-ε2ε3 genotype was significantly higher in controls than cases (14.3% vs. 6.1%, P=0.009, OR=0.39) whereas APOE-ε3ε4 genotype frequency was significantly higher in cases compared with controls (8.2% vs. 3.6%, P=0.03, OR=2.4). APOE-ε2 allele frequency in cases was significantly lower than that of controls (4.4% vs. 8.0%, P=0.03, OR=0.52). Also male controls were significantly more likely to have APOE-ε2 allele (7.8% vs. 1%, P=0.01, OR=0.11). APOE-ε4 allele frequency in cases was significantly higher than control group (4.8% versus 2.1%, P=0.03, OR=2.35). It seems that individuals carrying APOE-ε4 allele and/or APOE-ε3ε4 genotype develop MS two times more than non-carriers. Also APOE-ε2ε3 genotype or APOE-ε2 allele may have a protective role against MS development in Iranian population. Further investigation would be warranted to understand the role of APOE alleles and genotypes and risk of MS.
    Journal of the neurological sciences 06/2012; 320(1-2):22-5. DOI:10.1016/j.jns.2012.05.050 · 2.26 Impact Factor
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    • "Sensorimotor function was evaluated by scoring the vibrissae mediated forelimb placing reaction (Hoane et al., 2000; Hoane and Barth, 2001; Schallert and Woodlee, 2005; Barbre and Hoane, 2006). Each rat was held by the trunk ensuring the forelimbs were free to move. "
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    ABSTRACT: It has previously been shown that small peptide molecules derived from the apolipoprotein E (ApoE) receptor binding region are anti-inflammatory in nature and can improve outcome following head injury. The present study evaluated the preclinical efficacy of COG1410, a small molecule ApoE-mimetic peptide (1410 daltons), following cortical contusion injury (CCI). Animals were prepared with a unilateral CCI of the sensorimotor cortex (SMC) or sham procedure. Thirty mins post-CCI the animals received i.v. infusions of 0.8 mg/kg COG1410, 0.4 mg/kg COG1410, or vehicle. Starting on day 2, the animals were tested on a battery of behavioral measures to assess sensorimotor (vibrissae-forelimb placing and forelimb use-asymmetry), and motor (tapered balance beam) performance. Administration of the 0.8 mg/kg dose of COG1410 significantly improved recovery on the vibrissae-forelimb and limb asymmetry tests. However, no facilitation was observed on the tapered beam. The low dose (0.4 mg/kg) of COG1410 did not show any significant differences compared to vehicle. Lesion analysis revealed that the 0.8 mg/kg dose of COG1410 significantly reduced the size of the injury cavity compared to the 0.4 mg/kg dose and vehicle. The 0.8 mg/kg dose also reduced the number of glial fibrillary acid protein (GFAP+) reactive cells in the injured cortex. These results suggest that a single dose of COG1410 facilitates behavioral recovery and provides neuroprotection in a dose and task-dependent manner. Thus, the continued clinical development of ApoE based therapeutics is warranted and could represent a novel strategy for the treatment of traumatic brain injuries.
    Journal of Neurotrauma 08/2007; 24(7):1108-18. DOI:10.1089/neu.2006.0254 · 3.97 Impact Factor
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    • "It has been evidenced that apoE is involved in the autoimmune diseases. For example, the apoE e4 allele is associated with a progression of disability in MS (Chapman et al., 2001). ApoE deficiency exacerbated experimental allergic encephalomyelitis (EAE), an animal mode for MS, and EAN, as well as increased antigen specific T cell proliferation in both EAE and EAN (Karussis et al., 2003; Yu et al., 2004). "
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    ABSTRACT: Apolipoprotein E (apoE) has immunomodulatory properties and has been implicated in the pathogenic mechanism of autoimmune diseases. Previously, the authors found that apoE deficiency increased the susceptibility to experimental autoimmune neuritis (EAN), an animal model for human Guillain-Barré syndrome. To further elucidate the mechanism behind apoE deficiency exacerbating EAN, the authors investigated the role of major target and important antigen-presenting cells of the peripheral nerve system, Schwann cells (SCs), in apoE knockout mice. Treatment of apoE deficient SCs with recombinant mouse interferon-gamma and lipopolysaccharide resulted in higher MHC-II and CD40 expression as compared with normal SCs derived from wild-type mice. The increased MHC-II and CD40 expression on SCs was accompanied by lower levels of intracellular IL-6 production within SCs of apoE deficiency, which is confirmed by the neutralization with anti IL-6 antibody. The increased antigen-presenting capacity of apoE deficient SCs was further explored by enhancement of T cell proliferation co-cultured with P0 peptide 180-199 specific T cells derived from EAN mice immunized with the P0 peptide. In conclusion, apoE may protect mice from EAN and probably also from chronic inflammatory demyelinating polyneuropathy by affecting the antigen-presenting function of SCs via influence of IL-6 production.
    Glia 05/2007; 55(7):772-6. DOI:10.1002/glia.20498 · 6.03 Impact Factor
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