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Original Investigation
October 2017

Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis

Author Affiliations
  • 1Laboratory of Neuro Imaging, Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles
  • 2National Alzheimer’s Coordinating Center, University of Washington, Seattle
  • 3Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia
  • 4Coalition Against Major Disease, Critical Path Institute, Tucson, Arizona
  • 5IRCCS Fatebenefratelli, The National Centre for Alzheimer’s Disease, Brescia, Italy
  • 6University Hospitals and University of Geneva, Geneva, Switzerland
  • 7Department of Anatomy and Neurobiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 8Department Neurology and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 9Framingham Heart Study, Boston University Schools of Medicine and Public Health, Boston, Massachusetts
  • 10Department of Neurology, Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts
  • 11Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
  • 12University of Wisconsin School of Medicine and Public Health, Madison
  • 13Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan City, Taiwan
  • 14Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
  • 15Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
  • 16Dementia Center, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
  • 17Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, Taoyuan City, Taiwan
  • 18Department of Medical Imaging and Intervention, Keelung Branch, Chang Gung Memorial Hospital, Keelung City, Taiwan
JAMA Neurol. 2017;74(10):1178-1189. doi:10.1001/jamaneurol.2017.2188
Key Points

Question  Are female carriers of the apolipoprotein E ε4 allele at greater risk of developing Alzheimer disease than men?

Findings  In this meta-analysis of 27 independent research studies with 58 000 participants, women and men with 1 copy of apolipoprotein E ε4 did not show a difference in risk of Alzheimer disease from age 55 to 85 years. However, these women were at increased risk vs men between ages 65 and 75 years.

Meaning  Sex-specific treatments for cognitive decline and Alzheimer disease may need to be initiated a younger age, especially in those who carry an apolipoprotein E ε4 allele.

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.

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