Apolipoprotein E, gender, and Alzheimer's disease: an overlooked, but potent and promising interaction

Abstract

Alzheimer's disease (AD) is an increasingly prevalent, fatal neurodegenerative disease that has proven resistant, thus far, to all attempts to prevent it, forestall it, or slow its progression. The ε4 allele of the Apolipoprotein E gene (APOE4) is a potent genetic risk factor for sporadic and late-onset familial AD. While the link between APOE4 and AD is strong, many expected effects, like increasing the risk of conversion from MCI to AD, have not been widely replicable. One critical, and commonly overlooked, feature of the APOE4 link to AD is that several lines of evidence suggest it is far more pronounced in women than in men. Here we review previous literature on the APOE4 by gender interaction with a particular focus on imaging-related studies.

Figure 1. APOE4 risk is greater in women

Compared to background risk in APOE3 homozygotes, female APOE3/4 heterozygotes’ odds ratio peaks near 4 whereas the odds ratio in male APOE3/4 heterozygotes barely exceeds 1. The odds ratio for both men and women APOE4 homozygotes peaks near 10 though remains somewhat higher in women. (This is adapted from Figure 2 in the meta-analysis by Farrer and colleagues).

Figure 2

Gender modulates the APOE effect on default mode network connectivity. An ApoE by gender interaction was found in the precuneus region of the default mode network. The bar graph shows the mean parameter estimates for this cluster, for male and female E3 homozygotes and male and female E4 carriers. The greatest reduction was observed in the female 4 carriers. (This is adapted from Figure 3 of Damoiseaux et al.)