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APOE and Gender

APOE and Gender

Although APOE4 is a genetic risk factor for late-onset Alzheimer's disease, its effects may be different depending on whether you are a man or a woman.

Apolipoprotein E, known commonly as APOE, is a gene associated with varying risk of developing Alzheimer's, depending on which type (i.e., allele) you have. There are three different alleles—APOE2, APOE3, and APOE4. Everyone has two alleles, so there are six possible combinations: E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. People with E2/E2 have the lowest risk for Alzheimer’s, while those with E4/E4 have the highest risk.

APOE4 is a genetic risk factor for Alzheimer's disease for both men and women, but its magnitude and effect appears to differ between genders. For example, women with APOE4 are more likely than men to have worse memory performance [1], greater brain atrophy, and lower brain metabolism [2]. Women with APOE4 are also more likely to develop mild cognitive impairment or Alzheimer's disease than men with the allele [3][4]. And in APOE4 carriers with mild cognitive impairment, women have higher levels of biological markers associated with Alzheimer’s than men.

But it's not all bad news for women carrying APOE4. Elderly men diagnosed with mild cognitive impairment or Alzheimer's who were APOE4 carriers showed higher risks of microbleeds in the brain compared to APOE4-carrying women with the same condition [5]. Over 80% of Alzheimer's patients have at least a mild degree of a condition (i.e., cerebral amyloid angiopathy) that can cause bleeding in the brain [6]. Men with an APOE4 allele and Alzheimer's disease are more likely to have a severe form of this condition than women [7].

There is growing recognition that biological variables—such as genetics and gender—must be considered when developing effective disease treatments. In fact, the National Institutes of Health now require all federal research grant applications to account for gender differences in preclinical and clinical studies [8]. This research will further our understanding of how biological variables affect brain health and Alzheimer's disease and may also lead to individualized treatment options.

For now, if you carry the APOE4 allele there are several ways you can reduce your risk for Alzheimer's disease. APOE4 carriers are more likely to protect their brains by effectively managing hypertension [9] and diabetes [10] compared to non-carriers. And everyone, regardless of allele status, can reduce Alzheimer's risk by following our first steps to protect your cognitive vitality. If you know you carry the APOE4 allele or have been diagnosed with mild cognitive impairment or Alzheimer's disease, you can also volunteer for a clinical trial. Information is available on the clinical trials page at National Institute on Aging.


  1. Fleisher AS, Sun S, Taylor C et al. (2008) Volumetric MRI vs clinical predictors of Alzheimer disease in mild cognitive impairment. Neurology 70, 191-199.
  2. Sampedro F, Vilaplana E, de Leon MJ et al. (2015) APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls. Oncotarget 6, 26663-26674.
  3. Altmann A, Tian L, Henderson VW et al. (2014) Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 75, 563-573.
  4. Farrer LA, Cupples LA, Haines JL et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349-1356.
  5. Cacciottolo M, Christensen A, Moser A et al. (2016) The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice. Neurobiol Aging 37, 47-57.
  6. Ellis RJ, Olichney JM, Thal LJ et al. (1996) Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV. Neurology 46, 1592-1596.
  7. Shinohara M, Murray ME, Frank RD et al. (2016) Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer's disease. Acta Neuropathol 132, 225-234.
  8. (2015) Consideration of sex as a biological variable in NIH-funded research (PDF). NIH.
  9. Guo Z, Fratiglioni L, Viitanen M et al. (2001) Apolipoprotein E genotypes and the incidence of Alzheimer's disease among persons aged 75 years and older: variation by use of antihypertensive medication? Am J Epidemiol 153, 225-231.
  10. Vagelatos NT, Eslick GD (2013) Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev 35, 152-160.

Yuko Hara, PhD, is Director of Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation. Dr. Hara was previously an Assistant Professor in Neuroscience at the Icahn School of Medicine at Mount Sinai, where she remains an adjunct faculty member. Her research focused on brain aging, specifically how estrogens and reproductive aging influence the aging brain's synapses and mitochondria. She earned a doctorate in neurology and neuroscience at Weill Graduate School of Medical Sciences of Cornell University and a bachelor's degree in biology from Cornell University, with additional study at Keio University in Japan. Dr. Hara has authored numerous peer-reviewed publications, including articles in PNAS and Journal of Neuroscience.

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