Large Meta-Analysis Establishes the ACE Insertion-Deletion Polymorphism as a Marker of Alzheimer's Disease

• Published in: American journal of epidemiology Vol. 162; no. 4; pp. 305 - 317
• Main Authors: Lehmann, Donald J., Cortina-Borja, Mario, Warden, Donald R., Smith, A. David, Sleegers, Kristel, Prince, Jonathan A., van Duijn, Cornelia M., Kehoe, Patrick G.
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 15-08-2005; Oxford Publishing Limited (England)
• Subjects: ACE; Aged; Alzheimer disease; Alzheimer Disease - genetics; Alzheimer's disease; Analysis. Health state; angiotensin I-converting enzyme (gene); angiotensin I-converting enzyme (protein); APOE4; apolipoprotein E ε4 (allele); Apolipoprotein E4; Apolipoproteins E - genetics; Biological and medical sciences; Chromosome aberrations; Confidence Intervals; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enzymes; Epidemiology; Ethnic Groups; Female; General aspects; Genetic markers; Genetics; heterogeneity; Humans; Hybrid Vigor - genetics; Male; Medical genetics; Medical sciences; Medicin och hälsovetenskap; Meta-analysis; Middle Aged; Neurology; Peptidyl-Dipeptidase A - genetics; Polymorphism; Polymorphism, Genetic - genetics; Public health. Hygiene; Public health. Hygiene-occupational medicine; Human; Nervous system diseases; Enzyme; Alzheimer disease; Insertion; Biological marker; meta-analysis; Review; Epidemiology; Cerebral disorder; Metaanalysis; Peptidases; Heterogeneity; Apolipoprotein E; Peptidyl-dipeptidase A; Central nervous system disease; Deletion; Hydrolases; Peptidyl-dipeptidases; Degenerative disease; Public health; Polymorphism
• ISSN: 0002-9262; 1476-6256
• DOI: 10.1093/aje/kwi202

Apolipoprotein E ε4 (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 ε4 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.