IMPORTANCE It is unclear whether female carriers of the apolipoprotein E (APOE) epsilon 4 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 setswere 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 epsilon 3/epsilon 4 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 epsilon 3/epsilon 4 had an increased risk of AD compared with men with APOE epsilon 3/epsilon 3. The APOE epsilon 2/epsilon 3 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 e3/e4 (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 epsilon 4/epsilon 4 showed increased risks vs individuals with epsilon 3/epsilon 4, but no significant differences between men and women with epsilon 4/epsilon 4 were seen. CONCLUSIONS AND RELEVANCE Contrary to long-standing views, men and women with the APOE epsilon 3/epsilon 4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages. (C) 2017 American Medical Association. All rights reserved.