Association of APOE ε4 allele with survival in amyotrophic lateral sclerosis
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disorder affecting both the upper and the lower motor neurons. The pathogenesis of sporadic ALS, the most common form of disease, is unknown and probably multifactorial, including overexposure of motor neurons to glutamate and oxidative stress-induced cell death. Further causative factors, including a genetic predisposition, may have a modulatory influence [1].
The rate of progression of the disease is fast, but can differ strikingly among affected individuals, ranging from few months to 10 years or more. Older age and a bulbar form at disease onset are usually associated with more rapid deterioration.
Apolipoprotein E (ApoE) is a key regulator of plasma lipid levels, affecting all lipoproteins by modulating their clearance or their processing, as well as the production of hepatic very low density lipoproteins [2]. The human APOE gene has three common isoforms: ε2, ε3 and ε4. ApoE is produced in abundance in the brain, and it is the principal lipid transport protein there [3]. Roses [4] found that the APOE ε4 allele is a major susceptibility gene for Alzheimer's disease (AD), associated with about 50% of cases of sporadic and familial AD.
Because of the apparent similarities between AD and ALS regarding the pathogenesis of these diseases, several authors have studied the association of APOE ε4 and ALS, and reached conflicting results. Some studies [5], [6], [7], [8], [9] found the frequency of the APOE ε4 allele to be comparable to the allele frequency of the general population and did not find any association between the age at onset, site of onset, or duration of the disease in carriers or non-carriers of an APOE ε4 allele. In other studies, an APOE ε4 allele was associated with poor clinical outcome in ALS patients. One study showed a significantly shorter duration of disease for patients carrying the ε4 allele [10]; in another study, a significantly more rapid progression rate was seen in the initial stage of disease for patients with the ε4 allele [6]. Two other studies showed a trend toward shorter survival or more rapid disease progression for patients with the ε4 allele, but without statistical significance [7], [11]. A higher proportion of bulbar onset patients was also seen in APOE ε4 carriers [10], [11]. In the present study, we examined the APOE ε4 allele frequency in a large cohort of ALS patients and correlated its presence to survival.
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Patients and methods
The study included 100 consecutive sporadic ALS patients in Israel (53 males). Their mean age was 57±12 years, range 21 to 82 years. Of the 100 patients, 61 were Ashkenazi, 34 were non-Ashkenazi Jews and 5 were non-Jews. Twenty four patients had a bulbar form at onset; the remaining 76 had a limb onset. All patients were diagnosed as definite or probable ALS using the revised El Escorial criteria [12]. The frequency of the APOE ε4 allele in the ALS population was compared to a previously
Results
Table 1 shows the demographic data of patients with and without APOE ε4 alleles. There were 29 patients who had at least one APOE ε4 allele (2 were homozygotes). The frequency of APOE ε4 alleles in the ALS group was 15.1%, as opposed to only 10.9% in the control group [13]; however, this difference was not statistically significant (p=0.13, χ2 test). Patients with and without APOE ε4 alleles had similar male/female and Ashkenazi/non-Ashkenazi ratios. The age at onset in the two patient groups
Discussion
The main finding in the present study was that the APOE ε4 allele is associated with poor survival in ALS. There is a proven association between APOE ε4 allele and another neurodegenerative disease—AD [4], [13]. The APOE ε4 allele was also associated with poor clinical outcome after head injury [15], in dementia associated with stroke [16], [17] and with earlier age at onset of Wilson's disease [18]. However, in Parkinson's disease, there is no obvious relationship between clinical factors of
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