APOE- 2 allele associated with higher prevalence of sporadic Parkinson disease

Background: The link of the apolipoprotein (APOE) -ε4 allele to Alzheimer disease (AD) has led to studies investigating the role of apoE polymorphisms in Parkinson disease (PD). The authors hypothesized that any association between PD and APOE alleles and genotypes would be too small to be detected or precisely estimated by an individual case-controlled study. Method: The hypothesis was tested by systematic review and meta-analysis of results from casecontrol studies that provided clear clinical or pathologic criteria for PD and that reported APOE genotype frequencies. Published reports were obtained from MEDLINE, Biosis Previews, and ISI Web of Science searches, supplemented by citation analysis from retrieved articles. The authors estimated and compared prevalence odds ratios (OR) for PD in relation to each allele and genotype. Results: Twenty-two eligible studies were identified. There was no evidence of heterogeneity (p 0.4) or publication bias (p 0.2) for any allele or genotype. The estimated summary OR for one or more copies of each APOE allele was 1.20 for APOE-ε2 (95% CI, 1.02 to 1.42), 0.83 for APOE-ε3 (95% CI, 0.63 to 1.09), and 0.99 for APOE-ε4 (95% CI, 0.87 to 1.14). Conclusions: Unlike Alzheimer disease, for which the APOE-ε4 allele increases the prevalence and the APOE-ε2 allele is protective, the authors’ analysis shows the APOE-ε2 allele, but not the APOE-ε4 allele, to be positively associated with sporadic Parkinson disease. NEUROLOGY 2004;62:2198–2202 Apolipoprotein E (apoE for the protein, APOE for the gene) is a polymorphic plasma lipoprotein whose genes (19q13.2) have three alleles (APOE-ε2, APOEε3, and APOE-ε4), yielding six possible genotypes. The APOE-ε3 allele is predominant in all populations (reported prevalence, 0.49 to 0.91), with the APOE-ε2 (reported prevalence, 0.01 to 0.15) and APOE-ε4 (reported prevalence, 0.06 to 0.37) alleles less common. The APOE-ε4 allele is a major susceptibility gene for sporadic and familial Alzheimer disease (AD) and also has been associated with poor clinical outcome in patients with acute head trauma and stroke. In contrast, the APOE-ε2 allele seems to occur with lower frequency in AD and is associated with delayed onset of AD symptoms, actually occurring with higher frequency in centenarians. Thus, in multiple forms of neural injury or degenerative diseases, the APOE-ε4 allele has been postulated to either increase vulnerability or inhibit recovery, whereas the APOE-ε2 allele is considered protective.1 For these reasons, APOE polymorphisms, especially the APOE-ε4 allele, have been hypothesized to play a deleterious role in Parkinson disease (PD). The results from numerous case-control studies are inconsistent, with most authors reporting no significant associations between APOE alleles and PD.2-10 Because of the hypothesized multifactorial etiology of PD, each susceptibility gene would be expected to have only a modest association with the disease. We used meta-analysis to provide adequate power to detect weak associations. Methods. Source of data. We searched MEDLINE (PubMed), Biosis Previews, and ISI Web of Science databases for English language publications from January 1, 1966 to June 24, 2003 using the key words “Parkinson” and “apoE” or “apolipoprotein.” The search revealed 123 publications. Additional information was found by following the reference citations from retrieved articles. Two a priori inclusion criteria were 1) case-control studies in which the cases were defined as either clinically diagnosed or pathologically confirmed PD; and 2) information on genotype frequency was either contained in the article or obtainable from the original investigators. If the authors reported results in more than one publication, we used only the one with more comprehensive data. The following information was extracted (see table E-1 on the Neurology Web site) from each included study: sample size; APOE genotype; age and gender ratio of the subjects; the year of publication; and the country in which the study was conducted. Some desirable information was not available in most of these articles, including ethnicity of subjects, age at onset, clinical subtypes, and pathologic characteristics. Statistical analysis. Funnel plots of log case-control odds ratios (OR), a log-rank test,11 and the regression test12 were examined for evidence of publication bias. Overall homogeneity test p values were computed for the Cochran Q statistic. ORs for APOE alleles were calculated by contrasting persons who have at least one copy of the specified allele with those persons who have no copies. These analyses were conducted with and without adjustment for confounding among alleles. The adjusted analyses used the Mantel–Haenszel OR estimator to adjust, for Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of