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

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1 APOE- 2 allele associated with higher prevalence of sporadic Parkinson disease Xuemei Huang, MD, PhD; Peter C. Chen, BS; and Charles Poole, MPH, ScD Abstract 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: Additional material related to this article can be found on the Neurology Web site. Go to and scroll down the Table of Contents for the June 22 issue to find the title link for this article. 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 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 test 12 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 From the Department of Neurology, University of North Carolina School of Medicine, and the Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, NC. Supported in part by NIH grants AG21491 (to X.H.) and ES10126 (to C.P.). Received November 10, Accepted in final form February 18, Address correspondence and reprint requests to Dr. Xuemei Huang, Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC ; xuemei@med.unc.edu 2198 Copyright 2004 by AAN Enterprises, Inc.

2 Figure 1. Funnel plots of estimated odds ratios (ORs) for each allele in sporadic Parkinson disease. Consistent with a lack of publication bias, the OR for individual studies approach the summary OR as individual study variance decreases. example, for APOE-ε3 and APOE-ε4 to estimate the association between PD and the APOE-ε2 allele. Dose-response analyses were also conducted using a 0, 1, 2 scale for each allele, without adjustment for the other alleles. Because the results of the unadjusted analyses conformed closely to those of the dose-response analyses, the latter are not reported. ORs of APOE genotypes were estimated by contrasting persons with specific genotypes (e.g., the APOE-ε2ε3 allelic configuration). In these analyses, persons with two copies of the APOE-ε3 allele, the most common configuration, were placed into the reference category. To explore associations between characteristics of studies and their results, we performed stratified and meta-regression analyses. The dependent variable was the log OR, and the independent variables were the study characteristics. The meta-regressions were fit using random effects, inverse variance-weighted linear regression, with the among-studies variance estimated by restricted maximum likelihood. 13 The log OR was transformed back to the original ratio scale; the meta-regression coefficient estimates the ratio of the average OR in studies with one characteristic to the average OR with another characteristic. The following study characteristics were examined with cutoff points for binary variable specifications selected to achieve as close as possible to balanced distributions: year of publication (1996 or before, after 1996), geographic locale (Europe, Asia, and North America), average age of study participants ( 67 years, 67 years), and gender ( 50% male, 50% male). We also conducted a 2 test of Hardy Weinberg equilibrium (on 5 df) in the control group for each study. The test results created two natural groups of studies for stratified and metaregression analysis: one group including three studies had p 0.1, suggesting that the source populations were not in Hardy Weinberg equilibrium, and the other group including the remainder of the studies had p ,14,15 Given little or no evidence of publication bias, overall heterogeneity, or appreciable associations between study results and study characteristics, fixed effects summary OR estimates and 95% CIs were computed. We used the 95% confidence limit ratio (CLR), the ratio of the upper to lower 95% confidence limits, to gauge the precision of the summary estimates. All analyses were conducted using STATA versions 7 and 8 software (Stata, Inc., College Station, TX). Results. We identified 31 articles that met the first selection criterion; 21 of these articles reported complete genotype frequency information, whereas the remaining 10 reported only allele frequencies. After request, authors of 1 of these 10 articles provided genotype frequencies. 16 Consequently, our analysis is based on results from 22 independent studies whose attributes are listed in table E-1 (see table E-1 on the Neurology Web site), reflecting 2,157 patients and 7,831 control subjects. The APOE allele counts from the studies that could not be included are given in table E-2 (see table E-2 on the Neurology Web site). Neither visual inspection of funnel plots (figure 1) nor the tests of funnel plot symmetry gave any indication of publication bias (i.e., all p values from the log-rank test 11 and the regression test 12 were acceptably high; table). There was also little or no evidence of overall heterogeneity (p 0.8 in all instances; see table). Regarding the alleles of a priori interest, the APOE-ε4 allele showed no association with sporadic PD in the available literature as a whole (see figure 2, figure 3, and the table), whereas the APOE-ε2 allele had a positive association with sporadic PD. There was a suggestion of an inverse association between the APOE-ε3 allele and sporadic PD (see figure 2 Table Meta-analysis results for APOE alleles and genotypes in sporadic Parkinson s disease Alleles* Genotypes APOE Measure ε2 ε3 ε4 ε2ε2 ε2ε3 ε2ε4 ε3ε3 ε3ε4 ε4ε4 Homogeneity P Begg P Egger P Summary OR % CI ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 95% CLR * The odds ratios for the APOE alleles contrast persons who have at least one copy of the specified allele with persons who have no copies, unadjusted within studies for the other two alleles. For adjusted odds ratios, please refer to the text in the results section. The odds ratios for APOE genotypes contrast persons who have specified genotypes with persons who have ε3ε3 alleles the most common form of APOE genotypes. June (2 of 2) 2004 NEUROLOGY

3 Figure 2. Forest plots of the estimated odds ratios (ORs) for each allele in sporadic Parkinson disease. This figure shows the estimated ORs and 95% CI for each individual study. The y-axis is the year of publication and reference number (in parenthesis). and the table), but this association was less precise than those for the other two alleles, owing to the extremely high frequency of the APOE-ε3 allele (with 95% of control subjects having at least one copy of the APOE-ε3 allele in all studies combined). Moreover, whereas the results did not change in the allele-adjusted analyses for APOE-ε2 (adjusted OR 1.21; 95% CI, 1.02 to 1.45) or APOE-ε4 (adjusted OR 0.98; 95% CI, 0.85 to 1.14), the adjustment for APOE-ε2 and APOE-ε4 shifted the association between APOE-ε3 and sporadic PD to the null value (adjusted OR 1.01; 95% CI, 0.62 to 1.64). This change suggests that the unadjusted estimate for APOE-ε3 was confounded downward because of the inverse association of this allele with another allele (APOE-ε2) that has a positive association with sporadic PD. In the analysis of specific genotypes (see table) in which interallelic confounding cannot occur, the APOE-ε2ε4 configuration emerged as the only genotype markedly associated with sporadic PD, although a trend toward a positive association with APOE-ε2ε3 was seen. Year of publication, percentage of male participants, and average age were not associated with the OR estimates from the individual studies for any of the three alleles. For APOE-ε2, but not APOE-ε3 or APOE-ε4, there was a suggestion of a somewhat stronger positive association in studies done in Europe than elsewhere. Using only the 14 European studies, the summary estimate for the APOE-ε2 allele was OR 1.28 (95% CI, 1.06 to 1.54; homogeneity p 0.07). After deletion of the three studies with evidence among the control subjects that the source populations were not in Hardy Weinberg equilibrium, the positive association with APOE-ε2 also became slightly stronger, OR 1.23 (95% CI, 1.04 to 1.46; homogeneity p 0.8), than in all studies combined. Discussion. We estimated a positive association between the APOE-ε2 allele and sporadic PD and little or no association with APOE-ε3 or APOE-ε4 alleles, especially after adjusting for mutual confounding among the three alleles. The association seems to be specific for the APOE-ε2 allele because increased prevalence of sporadic PD appeared to be associated with the APOE-ε2ε4 (and possibly the 2200 NEUROLOGY 62 June (2 of 2) 2004 APOE-ε2ε3) genotypes, although such an association seems weaker for persons with the APOE-ε2ε3 genotype. The APOE-ε2ε2 genotype is rare in the covered populations (0.64% of control subjects), thus leading to the lowest precision in OR estimation. More research including special populations (if there are any) is needed to obtain a reasonably precise estimate of the association between sporadic PD and this uncommon genotype. As noted, one-third of the reports could not be included because only allele counts were reported. Nevertheless, we note that seven of these nine studies reported that the APOE-ε2 allele was more frequent among patients with PD than among control subjects (see table E-2 on the Neurology Web site). Our findings of the association of APOE-ε2 (not APOE-ε4) with increased prevalence of PD underscore a major pathophysiologic difference among neurodegenerative diseases such as PD and AD, often perceived as similar age-related disorders. In the past, consistent with their roles in AD, the APOE-ε2 and APOE-ε3 alleles have been demonstrated to facilitate neurite outgrowth, accumulate in neurons, 1 and inhibit apoptosis, 17 whereas the APOE-ε4 allele is less efficient in these regards. A process unrelated to apoe actions in neuronal repair and remodeling may also hold the clue for understanding its involvement in PD. There is evidence that other polymorphisms (e.g., N-acetyltransferase 2, monoamine oxidase B, glutathione transferase 1, and those on mitochondria trnaglu) may be associated with sporadic PD, underscoring the need to include the interplay of apoe and environmental factors to understand this sporadic disease. 18 In the past, almost every reported association of gene polymorphism and PD has been contradicted by other studies. 18 This includes the association of APOE-ε4 with different PD subgroups (such as PD dementia or familial PD) and with age at onset. 19,20 The present study demonstrates that the existing

4 Figure 3. Cumulative meta-analysis of estimated odds ratios (ORs) for APOE- 2 and APOE- 4 alleles in sporadic Parkinson disease. This figure illustrates that the precision increases and the 95% CI decreases as additional studies are added chronologically to the estimation of ORs. The y-axis is the year of publication and reference number (in parenthesis). literature as a whole (see figures 2, 3, and table E-2 on the Neurology Web site for references) supports a positive association between an APOE polymorphism and sporadic PD disease. Further study is needed to address age at onset and clinical subtype, including Lewy body disease as a potential clinical confounder. The importance of the current findings relates to understanding the interaction of complex factors in sporadic PD as opposed to a clinically diagnostic use. Although the association of APOE-ε2 with PD could be an epiphenomenon, there is increasing awareness of the role of apoe in diverse biologic processes in addition to apoptosis and cell repair. In addition, the field has been grappling with other PD paradoxes (e.g., protective effects of smoking and coffee in sporadic PD), and our results may well integrate into an unraveling of the complex origins of sporadic PD. Acknowledgment The authors thank Dr. Chris Morris for providing some of the original data. The authors also thank Drs. Richard Mailman, Frank Longo, Daniel Kaufer, Alexander Troster, and Kari North, and Professor Pierre Morell for the guidance and inspiration he offered just before his recent death. References 1. Mahley RW, Rall SC Jr. Apolipoprotein E. Far more than a lipid transport protein. Annu Rev Genomics Hum Genet 2000;1: Arai H, Muramatsu T, Higuchi S, Sasaki H, Trojanowski JQ. Apolipoprotein E gene in Parkinson s disease with or without dementia. 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Modulation of disease risk according to a cathepsin D/apolipoprotein E genotype in Parkinson s disease. J Neural Transm 2003;110: June (2 of 2) 2004 NEUROLOGY

5 34. Hardy J, Crook R, Prihar G, et al. Senile dementia of the Lewy body type has an apolipoprotein E epsilon 4 allele frequency intermediate between controls and Alzheimer s disease. Neurosci Lett 1994;182: St. Clair D. Apolipoprotein E gene in Parkinson s disease, Lewy body dementia and Alzheimer s disease. J Neural Transm Suppl 1997;51: Arai H, Higuchi S, Sasaki H. Apolipoprotein E genotyping and cerebrospinal fluid tau protein: implications for the clinical diagnosis of Alzheimer s disease. Gerontology 1997;43(suppl 1): Mattila PM, Koskela T, Roytta M, et al. Apolipoprotein E epsilon4 allele frequency is increased in Parkinson s disease only with co-existing Alzheimer pathology. Acta Neuropathol (Berl) 1998;96: Higuchi S, Matsushita S, Nakane J, et al. Alpha2-macroglobulin gene polymorphisms show racial diversity and are not associated with Alzheimer s disease. Neuroreport 2000;11: Galasko D, Salmon DP, Craig UK, et al. Clinical features and changing patterns of neurodegenerative disorders on Guam, Neurology 2002;58: VIDEO ALERT See the videos posted online: Postictal paresis in focal epilepsies incidence, duration, and causes: A video-eeg monitoring study P. Gallmetzer, F. Leutmezer, W. Serles, et al. Neurology 2004;62: MEG localization of language-specific cortex utilizing MR-FOCUSS S.M. Bowyer, J.E. Moran, K.M. Mason, et al. Neurology 2004;62: Ocular lateropulsion in Wallenberg syndrome J.S. Kim, S.Y. Moon, S.-H. Park, et al. Neurology 2004;62:2287 Rhythmic teeth grinding induced by temporal lobe seizures S. Meletti, G. Cantalupo, L. Volpi, et al. Neurology 2004;62: SISCOM localization of a seizure focus within a heterotopia R. Zimmerman, J. Sirven, M. Roarke, et al. Neurology 2004;62:2328 Parkinsonism due to Kernohan notch: Clinical, structural, and functional imaging correlates Andrew H. Evans, Sveto Gacinovic, Durval C. Costa, and Andrew J. Lees Neurology 2004;62: Access and search for the article. Click on Video to view NEUROLOGY 62 June (2 of 2) 2004

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