American Journal of Epidemiology Advance Access originally published online on July 20, 2005
American Journal of Epidemiology 2005 162(4):305-317; doi:10.1093/aje/kwi202
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META-ANALYSIS |
Large Meta-Analysis Establishes the ACE Insertion-Deletion Polymorphism as a Marker of Alzheimer's Disease
1 The Oxford Project to Investigate Memory and Ageing (OPTIMA), Department of Pharmacology, University of Oxford, Oxford, United Kingdom
2 Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, London, United Kingdom
3 Department of Epidemiology and Biostatistics, Erasmus MC, Rotterdam, the Netherlands
4 Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden
5 Care of the Elderly, Department of Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol, United Kingdom
Correspondence to D. J. Lehmann, University Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, United Kingdom (e-mail: donald.lehmann{at}pharm.ox.ac.uk).
Apolipoprotein E 
4 (APOE*4) is the only fully established susceptibility allele for Alzheimer's disease. One of the most studied candidates is the insertion (I)/deletion (D) polymorphism (indel) of the gene for angiotensin I-converting enzyme (ACE). This study aimed to clarify its association with Alzheimer's disease. The meta-analysis included 39 samples, comprising 6,037 cases of Alzheimer's disease and 12,099 controls, using mainly primary data. Potential interactions with gender, age, ethnic group, and carrier status of the apolipoprotein E 4 allele were all examined. D homozygotes were at reduced risk of Alzheimer's disease (odds ratio = 0.81, 95% confidence interval: 0.72, 0.90; corrected p = 0.0004); I homozygotes showed no association with Alzheimer's disease, while heterozygotes were at increased risk. Although there were clear differences among the three ethnic groups examined (North Europeans, South Caucasians, and East Asians), in all groups D homozygotes were at reduced risk. These results confirm the association of the angiotensin I-converting enzyme indel with Alzheimer's disease across diverse populations, although this is probably due to linkage disequilibrium with the true risk factor. Further, in North Europeans, both association and Hardy-Weinberg analysis suggested partial heterosis, that is, an increased risk for heterozygotes, due to a hidden interaction with another, as yet unknown, risk factor. This interaction warrants further investigation.
Alzheimer disease; heterogeneity; meta-analysis
Abbreviations: ACE, angiotensin I-converting enzyme (protein); ACE, angiotensin I-converting enzyme (gene); APOE*4, apolipoprotein E
4 (allele)
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