Apolipoprotein E (APOE) is a type of apolipoprotein involved in various biological processes, including lipoprotein transport, immunoregulation, and even cognition. The gene that encodes APOE is called APOE gene and is polymorphic, with three major alleles (ε2, ε3 and ε4) producing 6 common genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4). The ε3 allele is the most common allele, and the ε3/ε3 the most common genotype in humans.

The ε4 allele is a genetic risk factor for Alzheimer’s disease (AD), and for more than two decades the long-standing view has been that women who carry the ε4 allele(s) have a greater risk of developing late-onset AD than men with the same number of copies [1]. However, many studies have not found this sex-specific difference.

To gain additional insight on this topic, a team of researchers utilized resources from the Global Alzheimer’s Association Interactive Network and collected data from 27 independent research studies, totaling nearly 58,000 participants, for a large-scale meta-analysis [2]. The majority of participants were from North America and Europe. Due to insufficient numbers of minority groups, only non-Hispanic white individuals were included in the analysis.

Contrary to the prevalent view from the past, men and women 55-85 years of age with the APOE ε3/ε4 genotype had nearly the same degree of increased risk of developing AD and mild cognitive impairment (MCI) compared with those with the most common ε3/ε3 genotype. Other findings included:

  • Individuals with 2 copies of the APOE ε4 allele were at greater risk for developing AD than those with only 1 copy
  • Individuals who carried the ε2 allele(s) had a decreased risk for AD. The protective effect of the ε2 allele was stronger in women than in men
  • Among ε3/ε4 carriers, women had an increased risk of MCI between ages 55 and 70 years and an increased risk of AD between ages 65 and 75

This meta-analysis were based on Caucasians from the developed countries; therefore, the results should not be applied to other racial/ethnic groups. Also, due to incomplete information, effects of other risk factors such as cigarette smoking, hormone changes, alcohol intake, and family history were not assessed.  The study results were published in the journal JAMA Neurology (October 2017).

Why is this Clinically Relevant?

  • Contrary to earlier views, both men and women age 55-85 years with ε3/ε4 genotype had similar increased risk of AD compared with those with ε3/ε3 genotype
  • However, these women were at increased risk vs. men at a younger age (65-75 years)
  • Treatments for AD and MCI may need to be initiated at younger age for women who carry the APOE ε4 allele(s)

Click here to read the JAMA Neurology abstract


[1]  Farrer, L.A., et al., 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, 1997. 278(16): p. 1349-56.

[2] Neu, S.C., et al., Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol, 2017. 74(10): p. 1178-1189.

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