Interestingly, this SNP retains significance in APOE∗E4 non-carriers, suggesting that increased risk of AD is independent of the effects of APOE. This supports the hypothesis that decreased androgen signaling, whether through genetic variants that decrease AR expression or low plasma testosterone levels, is a risk factor for AD, and that the androgen pathway may contribute to some of the missing heritability of AD risk. Here, APOE is linked to Alzheimer disease.