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October 22, 1997

Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis

Author Affiliations

for the APOE and Alzheimer Disease Meta Analysis Consortium
From the Departments of Neurology (Drs Farrer and Myers) and Epidemiology and Biostatistics (Drs Farrer and Cupples), Boston University School of Medicine, Boston, Mass; Molecular Neurogenetics Unit (Dr Haines) and Department of Neurology (Drs Haines and Hyman), Massachusetts General Hospital, Boston; Department of Epidemiology, University of Washington, Seattle (Dr Kukull); Gertrude H. Sergievsky Center and Department of Neurology, Columbia University, New York, NY (Dr Mayeux); Division of Neurology, Duke University Medical Center, Durham, NC (Dr Pericak-Vance); Department of Genetics, Stanford University School of Medicine, Stanford, Calif (Dr Risch); and Department of Epidemiology, Erasmus University, Rotterdam, the Netherlands (Dr van Duijn).
Dr Haines is associated with Athena Neurosciences, San Francisco, Calif, for the commercial use of the apolipoprotein E test as a diagnostic tool and as a result may receive future income from the use of this test.

JAMA. 1997;278(16):1349-1356. doi:10.1001/jama.1997.03550160069041

Objective.  —To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations.

Data Sources.  —Forty research teams contributed data on APOEgenotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources.

Main Outcome Measures.  —Odds ratios (ORs) and 95% confidence intervals (Cls) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes ∈2/∈2,∈2/∈3,∈2/∈4,∈3/∈4 and ∈4/∈4 relative to the ∈3/∈3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures.

Results.  —Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes ∈2/∈4 (OR=2.6, 95% Cl=1.6-4.0), ∈3/∈4 (OR=3.2, 95% Cl=2.8-3.8), and ∈4/∈4 (OR=14.9, 95% CI=10.8-20.6); whereas, the ORs were decreased for people with genotypes ∈2/∈2 (OR=0.6, 95% Cl=0.2-2.0) and ∈2/∈3 (OR=0.6, 95% Cl=0.5-0.8). The APOE ∈4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE ∈4—AD association in Japanese subjects was stronger than in Caucasian subjects (∈3/∈4: OR=5.6, 95% Cl=3.9-8.0; ∈4/∈4: OR=33.1, 95% Cl=13.6-80.5). The ∈2/∈3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE∈4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex.

Conclusions.  —The APOE∈4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE∈4 and AD in African Americans requires clarification, and the attenuated effect of APOE∈4 in Hispanics should be investigated further.

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