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August 28, 2017

Apolipoprotein E ε4 and Risk Factors for Alzheimer Disease—Let’s Talk About Sex

Author Affiliations
  • 1Department of Neurology, Biomedical Sciences Graduate Program and Weill Institute for Neurosciences, University of California, San Francisco
  • 2Section Editor, JAMA Neurology
JAMA Neurol. Published online August 28, 2017. doi:10.1001/jamaneurol.2017.1470

The apolipoprotein E ε4 (APOE4) allele is the most potent genetic risk factor for late-onset Alzheimer disease (AD) and female sex is associated with increased risk. In both sexes, carriers of the APOE4 allele harbor a dose-dependent increase in risk of AD development, compared with those with the neutral APOE3 or protective APOE2. We understand the APOE4 risk to be greater in women, and our current dogma raises several questions. Is female vulnerability to APOE4 a robust association in AD? If so, what mechanisms underlie the sex difference? Most importantly, is this sex difference of real consequence to human health?

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