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Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis.
JAMA Neurol. 2017 10 01; 74(10):1178-1189.JN

Abstract

Importance

It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established.

Objective

To determine how sex and APOE genotype affect the risks for developing MCI and AD.

Data Sources

Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants.

Study Selection

Non-Hispanic white individuals with clinical diagnostic and APOE genotype data.

Data Extraction and Synthesis

Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks.

Main Outcomes and Measures

Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes.

Results

Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE ε4/ε4 showed increased risks vs individuals with ε3/ε4, but no significant differences between men and women with ε4/ε4 were seen.

Conclusions and Relevance

Contrary to long-standing views, men and women with the APOE ε3/ε4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.

Links

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Authors+Show Affiliations

Neu SC
Laboratory of Neuro Imaging, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles.
Pa J
Laboratory of Neuro Imaging, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles.
Kukull W
National Alzheimer's Coordinating Center, University of Washington, Seattle.
Beekly D
National Alzheimer's Coordinating Center, University of Washington, Seattle.
Kuzma A
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
Gangadharan P
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
Wang LS
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
Romero K
Coalition Against Major Disease, Critical Path Institute, Tucson, Arizona.
Arneric SP
Coalition Against Major Disease, Critical Path Institute, Tucson, Arizona.
Redolfi A
IRCCS Fatebenefratelli, The National Centre for Alzheimer's Disease, Brescia, Italy.
Orlandi D
IRCCS Fatebenefratelli, The National Centre for Alzheimer's Disease, Brescia, Italy.
Frisoni GB
IRCCS Fatebenefratelli, The National Centre for Alzheimer's Disease, Brescia, Italy. University Hospitals and University of Geneva, Geneva, Switzerland.
Au R
Department of Anatomy and Neurobiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts. Department Neurology and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts. Framingham Heart Study, Boston University Schools of Medicine and Public Health, Boston, Massachusetts.
Devine S
Department of Neurology, Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts.
Auerbach S
Department of Neurology, Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts.
Espinosa A
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
Boada M
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
Ruiz A
Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
Johnson SC
University of Wisconsin School of Medicine and Public Health, Madison.
Koscik R
University of Wisconsin School of Medicine and Public Health, Madison.
Wang JJ
Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City, Taiwan. Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan.
Hsu WC
Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan. Dementia Center, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan.
Chen YL
Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan. Department of Medical Imaging and Intervention, Keelung Branch, Chang Gung Memorial Hospital, Keelung City, Taiwan.
Toga AW
Laboratory of Neuro Imaging, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles.

MeSH

AgedAged, 80 and overAlzheimer DiseaseApolipoproteins ECase-Control StudiesDatabases, FactualFemaleHumansLogistic ModelsMaleMiddle AgedRisk FactorsSex Characteristics

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28846757

Citation

Neu, Scott C., et al. "Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: a Meta-analysis." JAMA Neurology, vol. 74, no. 10, 2017, pp. 1178-1189.
Neu SC, Pa J, Kukull W, et al. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol. 2017;74(10):1178-1189.
Neu, S. C., Pa, J., Kukull, W., Beekly, D., Kuzma, A., Gangadharan, P., Wang, L. S., Romero, K., Arneric, S. P., Redolfi, A., Orlandi, D., Frisoni, G. B., Au, R., Devine, S., Auerbach, S., Espinosa, A., Boada, M., Ruiz, A., Johnson, S. C., ... Toga, A. W. (2017). Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurology, 74(10), 1178-1189. https://doi.org/10.1001/jamaneurol.2017.2188
Neu SC, et al. Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: a Meta-analysis. JAMA Neurol. 2017 10 1;74(10):1178-1189. PubMed PMID: 28846757.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. AU - Neu,Scott C, AU - Pa,Judy, AU - Kukull,Walter, AU - Beekly,Duane, AU - Kuzma,Amanda, AU - Gangadharan,Prabhakaran, AU - Wang,Li-San, AU - Romero,Klaus, AU - Arneric,Stephen P, AU - Redolfi,Alberto, AU - Orlandi,Daniele, AU - Frisoni,Giovanni B, AU - Au,Rhoda, AU - Devine,Sherral, AU - Auerbach,Sanford, AU - Espinosa,Ana, AU - Boada,Mercè, AU - Ruiz,Agustín, AU - Johnson,Sterling C, AU - Koscik,Rebecca, AU - Wang,Jiun-Jie, AU - Hsu,Wen-Chuin, AU - Chen,Yao-Liang, AU - Toga,Arthur W, PY - 2017/8/29/pubmed PY - 2017/10/19/medline PY - 2017/8/29/entrez SP - 1178 EP - 1189 JF - JAMA neurology JO - JAMA Neurol VL - 74 IS - 10 N2 - Importance: It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective: To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data Sources: Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants. Study Selection: Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data Extraction and Synthesis: Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main Outcomes and Measures: Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results: Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE ε4/ε4 showed increased risks vs individuals with ε3/ε4, but no significant differences between men and women with ε4/ε4 were seen. Conclusions and Relevance: Contrary to long-standing views, men and women with the APOE ε3/ε4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages. SN - 2168-6157 UR - https://www.unboundmedicine.com/medline/citation/28846757/Apolipoprotein_E_Genotype_and_Sex_Risk_Factors_for_Alzheimer_Disease:_A_Meta_analysis_ DB - PRIME DP - Unbound Medicine ER -