This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Related letter  • Similar articles in JAMA  Social Bookmarking   What's this?

A Meta-analysis

Lindsay A. Farrer, PhD; L. Adrienne Cupples, PhD; Jonathan L. Haines, PhD; Bradley Hyman, MD, PhD; Walter A. Kukull, PhD; Richard Mayeux, MD; Richard H. Myers, PhD; Margaret A. Pericak-Vance, PhD; Neil Risch, PhD; Cornelia M. van Duijn, PhD

JAMA. 1997;278(16):1349-1356.

Abstract
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 APOE4 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 APOE4 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 APOE4 and AD in African Americans requires clarification, and the attenuated effect of APOE4 in Hispanics should be investigated further.

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.

Footnotes
A complete listing of the APOE and Alzheimer Disease Meta Analysis Consortium appears at the end of this article.

Reprints; Lindsay A. Farrer, PhD, Department of Neurology, Boston University School of Medicine, 80 E Concord St, Boston, MA 02118 (e-mail: farrer@neugen.bu.edu).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED LETTER

Effects of Age and Ethnicity on the Link Between APOE 4 and Alzheimer Disease
Douglas C. Ewbank, Marie-Florence Shadlen, Lindsay A. Farrer, L. Adrienne Cupples, Richard H. Myers, Cornelia M. van Duijn, Richard Mayeux, Jonathan L. Haines, Walter A. Kukull, Bradley Hyman, Margaret A. Pericak-Vance, and Neil Risch
JAMA. 1998;279(8):580-582.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Patients With Alzheimer Disease Have Altered Transmitral Flow: Echocardiographic Analysis of the Vortex Formation Time
Belohlavek et al.
J Ultrasound Med 2009;28:1493-1500.
ABSTRACT | FULL TEXT  

Effects of Family History and Apolipoprotein E {varepsilon}4 Status on Cognitive Decline in the Absence of Alzheimer Dementia: The Cache County Study
Hayden et al.
Arch Neurol 2009;66:1378-1383.
ABSTRACT | FULL TEXT  

Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates
Sieh et al.
Hum Mol Genet 2009;18:3725-3738.
ABSTRACT | FULL TEXT  

Disclosure of APOE Genotype for Risk of Alzheimer's Disease
Green et al.
NEJM 2009;361:245-254.
ABSTRACT | FULL TEXT  

Symptoms of Depression and Anxiety After Delirium
Davydow
Psychosomatics 2009;50:309-316.
ABSTRACT | FULL TEXT  

Human APOE Isoform-Dependent Effects on Brain {beta}-Amyloid Levels in PDAPP Transgenic Mice
Bales et al.
J. Neurosci. 2009;29:6771-6779.
ABSTRACT | FULL TEXT  

Early parental death and late-life dementia risk: findings from the Cache County Study
Norton et al.
Age Ageing 2009;38:340-343.
FULL TEXT  

Fibrillar amyloid-{beta} burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease
Reiman et al.
Proc. Natl. Acad. Sci. USA 2009;106:6820-6825.
ABSTRACT | FULL TEXT  

Understanding the Association of Apolipoprotein E4 with Alzheimer Disease: Clues from Its Structure
Zhong and Weisgraber
J. Biol. Chem. 2009;284:6027-6031.
ABSTRACT | FULL TEXT  

Voxel-based analysis of cerebral glucose metabolism in mono- and dizygotic twins discordant for Alzheimer disease
Virta et al.
J. Neurol. Neurosurg. Psychiatry 2009;80:259-266.
ABSTRACT | FULL TEXT  

Declining brain glucose metabolism in normal individuals with a maternal history of Alzheimer disease
Mosconi et al.
Neurology 2009;72:513-520.
ABSTRACT | FULL TEXT  

APOE-{epsilon}4, Depressive Symptoms, and Cognitive Decline in Chinese Older Adults: Singapore Longitudinal Aging Studies
Niti et al.
J Gerontol A Biol Sci Med Sci 2009;64A:306-311.
ABSTRACT | FULL TEXT  

Vascular risk factors and dementia: How to move forward?
Viswanathan et al.
Neurology 2009;72:368-374.
ABSTRACT | FULL TEXT  

How to Use an Article About Genetic Association: B: Are the Results of the Study Valid?
Attia et al.
JAMA 2009;301:191-197.
ABSTRACT | FULL TEXT  

Alzheimer disease: Time to improve its diagnosis and treatment
SALLOWAY and CORREIA
Cleveland Clinic Journal of Medicine 2009;76:49-58.
ABSTRACT | FULL TEXT  

The Importance of Gene--Environment Interaction: Implications for Social Scientists
North and Martin
Sociological Methods Research 2008;37:164-200.
ABSTRACT  

Dementia of the Alzheimer Type
Jalbert et al.
Epidemiol Rev 2008;30:15-34.
ABSTRACT | FULL TEXT  

Genome-wide association studies: potential next steps on a genetic journey
McCarthy and Hirschhorn
Hum Mol Genet 2008;17:R156-R165.
ABSTRACT | FULL TEXT  

Evidence that the gene encoding insulin degrading enzyme influences human lifespan
Hong et al.
Hum Mol Genet 2008;17:2370-2378.
ABSTRACT | FULL TEXT  

Genes contributing to prion pathogenesis
Tamguney et al.
J. Gen. Virol. 2008;89:1777-1788.
ABSTRACT | FULL TEXT  

Deficiency of the INCL protein Ppt1 results in changes in ectopic F1-ATP synthase and altered cholesterol metabolism
Lyly et al.
Hum Mol Genet 2008;17:1406-1417.
ABSTRACT | FULL TEXT  

Genetic tests for common diseases: new insights, old concerns
Melzer et al.
BMJ 2008;336:590-593.
FULL TEXT  

Lack of Association Between Apolipoprotein E Polymorphism and Vascular Dementia in Koreans
Ki Woong Kim et al.
J Geriatr Psychiatry Neurol 2008;21:12-17.
ABSTRACT  

Plasma amyloid {beta} protein is elevated in late-onset Alzheimer disease families
Ertekin-Taner et al.
Neurology 2008;70:596-606.
ABSTRACT | FULL TEXT  

MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment
Whitwell et al.
Neurology 2008;70:512-520.
ABSTRACT | FULL TEXT  

From the Cover: Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism
Mosconi et al.
Proc. Natl. Acad. Sci. USA 2007;104:19067-19072.
ABSTRACT | FULL TEXT  

Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's disease
Hamshere et al.
Hum Mol Genet 2007;16:2703-2712.
ABSTRACT | FULL TEXT  

BEYOND AMYLOID: The Next Generation of Alzheimer's Disease Therapeutics
Seabrook et al.
Mol. Interv. 2007;7:261-270.
ABSTRACT | FULL TEXT  

The Pathogenesis of Alzheimers Disease Is It a Lifelong "Calciumopathy"?
Stutzmann
Neuroscientist 2007;13:546-559.
ABSTRACT  

Relation between smoking and risk of dementia and Alzheimer disease: The Rotterdam Study
Reitz et al.
Neurology 2007;69:998-1005.
ABSTRACT | FULL TEXT  

Cognitive Domain Decline in Healthy Apolipoprotein E {varepsilon}4 Homozygotes Before the Diagnosis of Mild Cognitive Impairment
Caselli et al.
Arch Neurol 2007;64:1306-1311.
ABSTRACT | FULL TEXT  

No association of CSF biomarkers with APOE{varepsilon}4, plaque and tangle burden in definite Alzheimer's disease
Engelborghs et al.
Brain 2007;130:2320-2326.
ABSTRACT | FULL TEXT  

Dopamine Genes and Schizophrenia: Case Closed or Evidence Pending?
Talkowski et al.
Schizophr Bull 2007;33:1071-1081.
ABSTRACT | FULL TEXT  

Plasma Homocysteine Is Associated with the Risk of Mild Cognitive Impairment in an Elderly Korean Population
Kim et al.
J. Nutr. 2007;137:2093-2097.
ABSTRACT | FULL TEXT  

Differences in the Association Between Apolipoprotein E Genotype and Mortality Across Populations
Ewbank
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2007;62:899-907.
ABSTRACT | FULL TEXT  

Apolipoprotein E genotypes and their relation to lipid levels in a rural South African population 1
Masemola et al.
Scand J Public Health 2007;35:60-65.
ABSTRACT  

Neuropsychological Measures in Normal Individuals That Predict Subsequent Cognitive Decline
Blacker et al.
Arch Neurol 2007;64:862-871.
ABSTRACT | FULL TEXT  

Invited Commentary: When Bad Genes Look Good--APOE*E4, Cognitive Decline, and Diagnostic Thresholds
Glymour
Am J Epidemiol 2007;165:1239-1246.
ABSTRACT | FULL TEXT  

Prevalence of dementia in Chamorros on Guam: Relationship to age, gender, education, and APOE
Galasko et al.
Neurology 2007;68:1772-1781.
ABSTRACT | FULL TEXT  

Ethnicity-specific Gene-Gene Interaction between IL-13 and IL-4R{alpha} among African Americans with Asthma
Battle et al.
Am. J. Respir. Crit. Care Med. 2007;175:881-887.
ABSTRACT | FULL TEXT  

How migraines impact cognitive function: Findings from the Baltimore ECA
Kalaydjian et al.
Neurology 2007;68:1417-1424.
ABSTRACT | FULL TEXT  

Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus
Graham et al.
Proc. Natl. Acad. Sci. USA 2007;104:6758-6763.
ABSTRACT | FULL TEXT  

Measuring the Risk of Alzheimer Disease
Rosenberg
Arch Neurol 2007;64:479-480.
FULL TEXT  

Cholesterol and Triglycerides Moderate the Effect of Apolipoprotein E on Memory Functioning in Older Adults
de Frias et al.
Journals of Gerontology Series B: Psychological Sciences and Social Science 2007;62:P112-P118.
ABSTRACT | FULL TEXT  

Less Atherosclerosis and Lower Blood Pressure for a Meaningful Life Perspective With More Brain
Staessen et al.
Hypertension 2007;49:389-400.
FULL TEXT  

Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia
Sundar et al.
Hum Mol Genet 2007;16:295-306.
ABSTRACT | FULL TEXT  

The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between {beta}-amyloid production and tau phosphorylation in Alzheimer disease
Kimura et al.
Hum Mol Genet 2007;16:15-23.
ABSTRACT | FULL TEXT  

The Effect of Borderline Diabetes on the Risk of Dementia and Alzheimer's Disease
Xu et al.
Diabetes 2007;56:211-216.
ABSTRACT | FULL TEXT  

Lower Prevalence of Epsilon 4 Allele of Apolipoprotein E Gene in Healthy, Longer-Lived Individuals of Hellenic Origin
Stakias et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2006;61:1228-1231.
ABSTRACT | FULL TEXT  

Human telomere biology: pitfalls of moving from the laboratory to epidemiology
Aviv et al.
Int J Epidemiol 2006;35:1424-1429.
ABSTRACT | FULL TEXT  

Primary prevention trials in Alzheimer disease.
Green and DeKosky
Neurology 2006;67:S2-S5.
ABSTRACT | FULL TEXT  

Prevention trials in Alzheimer disease: One step forward?
Touchon et al.
Neurology 2006;67:S21-S22.
ABSTRACT | FULL TEXT  

Activation of estrogen receptor {alpha} increases and estrogen receptor beta decreases apolipoprotein E expression in hippocampus in vitro and in vivo
Wang et al.
Proc. Natl. Acad. Sci. USA 2006;103:16983-16988.
ABSTRACT | FULL TEXT  

100 Years and Counting: Prospects for Defeating Alzheimer's Disease
Roberson and Mucke
Science 2006;314:781-784.
ABSTRACT | FULL TEXT  

Ashkenazi Jews and Breast Cancer: The Consequences of Linking Ethnic Identity to Genetic Disease
Brandt-Rauf et al.
AJPH 2006;96:1979-1988.
ABSTRACT | FULL TEXT  

Apolipoprotein E {varepsilon}4 and Age at Onset of Sporadic and Familial Alzheimer Disease in Caribbean Hispanics
Olarte et al.
Arch Neurol 2006;63:1586-1590.
ABSTRACT | FULL TEXT  

Regional brain atrophy in cognitively intact adults with a single APOE {varepsilon}4 allele.
Wishart et al.
Neurology 2006;67:1221-1224.
ABSTRACT | FULL TEXT  

Implications of Small Effect Sizes of Individual Genetic Variants on the Design and Interpretation of Genetic Association Studies of Complex Diseases
Ioannidis et al.
Am J Epidemiol 2006;164:609-614.
ABSTRACT | FULL TEXT  

Geographic Ancestry, Angiotensinogen Gene Polymorphism, and Cardiovascular Risk
Castellano
Hypertension 2006;48:562-563.
FULL TEXT  

Systematic review and meta-analysis of the association between complementary factor H Y402H polymorphisms and age-related macular degeneration
Thakkinstian et al.
Hum Mol Genet 2006;15:2784-2790.
ABSTRACT | FULL TEXT  

Hippocampal volume, brain atrophy, and APOE genotype after traumatic brain injury.
Isoniemi et al.
Neurology 2006;67:756-760.
ABSTRACT | FULL TEXT  

Genetics and Dementia Nosology
Blacker and Lovestone
J Geriatr Psychiatry Neurol 2006;19:186-191.
ABSTRACT  

"A Gene for. . .":The Nature of Gene Action in Psychiatric Disorders
Kendler
Focus 2006;4:391.
ABSTRACT | FULL TEXT  

Apolipoprotein E {varepsilon}4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference. The Hordaland Health Study
Lehmann et al.
J. Neurol. Neurosurg. Psychiatry 2006;77:902-908.
ABSTRACT | FULL TEXT  

When it runs in the family: putting susceptibility genes in perspective
Lock et al.
Public Understanding of Science 2006;15:277-300.
ABSTRACT  

Effect of apolipoprotein e on the cerebral load of latent herpes simplex virus type 1 DNA.
Burgos et al.
J. Virol. 2006;80:5383-5387.
ABSTRACT | FULL TEXT  

Commentary: Grading the credibility of molecular evidence for complex diseases
Ioannidis
Int J Epidemiol 2006;35:572-578.
FULL TEXT  

Structural and Functional Variations in Human Apolipoprotein E3 and E4
Chou et al.
J. Biol. Chem. 2006;281:13333-13344.
ABSTRACT | FULL TEXT  

Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus.
Xu et al.
J. Neurosci. 2006;26:4985-4994.
ABSTRACT | FULL TEXT  

Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice.
Esposito et al.
J. Neurosci. 2006;26:5167-5179.
ABSTRACT | FULL TEXT  

APOE epsilon variation in multiple sclerosis susceptibility and disease severity: Some answers
Burwick et al.
Neurology 2006;66:1373-1383.
ABSTRACT | FULL TEXT  

Reduced functional brain activity response in cognitively intact apolipoprotein E {varepsilon}4 carriers
Lind et al.
Brain 2006;129:1240-1248.
ABSTRACT | FULL TEXT  

The distribution of apolipoprotein E alleles in Scottish perinatal deaths
Becher et al.
J. Med. Genet. 2006;43:414-418.
ABSTRACT | FULL TEXT  

Inaugural Article: Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer's disease
Mahley et al.
Proc. Natl. Acad. Sci. USA 2006;103:5644-5651.
ABSTRACT | FULL TEXT  

Clinical trials in mild cognitive impairment: lessons for the future
Jelic et al.
J. Neurol. Neurosurg. Psychiatry 2006;77:429-438.
ABSTRACT | FULL TEXT  

Race and ethnicity in the era of emerging pharmacogenomics.
Harty et al.
J Clin Pharmacol 2006;46:405-407.
ABSTRACT | FULL TEXT  

Association of apolipoprotein e genotype and Alzheimer disease in african americans.
Murrell et al.
Arch Neurol 2006;63:431-434.
ABSTRACT | FULL TEXT  

Role of Genes and Environments for Explaining Alzheimer Disease
Gatz et al.
Arch Gen Psychiatry 2006;63:168-174.
ABSTRACT | FULL TEXT  

Dementia and Cerebrovascular Disease
Knopman
Mayo Clin Proc. 2006;81:223-230.
ABSTRACT | FULL TEXT  

Cholesterol, APOE genotype, and Alzheimer disease: An epidemiologic study of Nigerian Yoruba
Hall et al.
Neurology 2006;66:223-227.
ABSTRACT | FULL TEXT  

Heart Disease and Dementia: A Population-based Study
Bursi et al.
Am J Epidemiol 2006;163:135-141.
ABSTRACT | FULL TEXT  

Polymorphisms in the PON gene cluster are associated with Alzheimer disease
Erlich et al.
Hum Mol Genet 2006;15:77-85.
ABSTRACT | FULL TEXT  

Apolipoprotein E Genotype and Age-Related Myelin Breakdown in Healthy Individuals: Implications for Cognitive Decline and Dementia
Bartzokis et al.
Arch Gen Psychiatry 2006;63:63-72.
ABSTRACT | FULL TEXT  

Apolipoprotein E Genotype Modifies the Phenotype of Alzheimer Disease
Schott et al.
Arch Neurol 2006;63:155-156.
FULL TEXT  

APOE alleles predict the rate of cognitive decline in Alzheimer disease: A nonlinear model
Martins et al.
Neurology 2005;65:1888-1893.
ABSTRACT | FULL TEXT  

Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity
Chang et al.
Proc. Natl. Acad. Sci. USA 2005;102:18694-18699.
ABSTRACT | FULL TEXT  

Apolipoprotein (apo) E4 enhances amyloid {beta} peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target
Ye et al.
Proc. Natl. Acad. Sci. USA 2005;102:18700-18705.
ABSTRACT | FULL TEXT  

Children of Alzheimer Patients: An Overview
Jarvik and Blazer
J Geriatr Psychiatry Neurol 2005;18:181-186.
 

Genetic Risk Assessment for Adult Children of People With Alzheimer's Disease: The Risk Evaluation and Education for Alzheimer's Disease (REVEAL) Study
Roberts et al.
J Geriatr Psychiatry Neurol 2005;18:250-255.
ABSTRACT  

Genetic Heterogeneity in Association of the SUMO4 M55V Variant With Susceptibility to Type 1 Diabetes
Noso et al.
Diabetes 2005;54:3582-3586.
ABSTRACT | FULL TEXT  

Genetic susceptibility for Alzheimer's disease: Why did adult offspring seek testing?
Hurley et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2005;20:374-381.
ABSTRACT  

Modulation of Apolipoprotein E Structure by Domain Interaction: DIFFERENCES IN LIPID-BOUND AND LIPID-FREE FORMS
Hatters et al.
J. Biol. Chem. 2005;280:34288-34295.
ABSTRACT | FULL TEXT  

Shared genetic risk factors for obstructive sleep apnea and obesity
Patel
J. Appl. Physiol. 2005;99:1600-1606.
ABSTRACT | FULL TEXT