Basic Science and Pathogenesis

Although Alzheimer's disease (AD) is more prevalent in women than men, women's survival advantage may not fully account for the AD-related sex disparities. With studies suggesting a high genetic heritability for AD, exploring the genetic architecture behind sex differences in susceptibility to AD and its risk factors could enhance the understanding of disease mechanism.

We conducted genome-wide association studies (GWAS) and pleiotropic meta-analysis of AD and its risk factor-diabetes mellitus (DM)-in men and women of European ancestry. The AD GWAS focused on 172,097 men (including 8,445 cases) and 204,904 women (11,376 cases) from 10 studies. The DM GWAS included 165,287 men (24,154 cases) and 195,190 women (16,885 cases) from seven studies. The analyses leveraged strong genetic associations with DM to uncover weaker associations with AD.

GWAS of DM identified 30 men-specific loci on 15 chromosomes characterized by the genome-wide significant effects in men p_men<5×10^-8 and weak effects with p_women>10^-4 in women. Of them, there were eight loci mapped to THADA, NYAP2, IGF2BP2, HLA, DGKB, NUCB2, HMGA2, and CLEC14A gene clusters with men-specific pleiotropic effects in which associations with AD attained p_men<0.05 and p_women>0.05. For women, we identified 16 loci on 11 chromosomes with p_men>10^-4 and p_women<5×10^-8. Women-specific pleiotropic associations (p_men>0.05 and p_women<0.05) were observed in two gene clusters (HNF1B, CDKN2B). Female carriers of the APOE ε4 allele were at significantly higher AD risk (β=1.29, 95% confidence interval [CI]=1.24;1.33) than male carriers (β=1.12, CI=1.06;1.17). The ε4 allele was favorably associated with DM in both men (β=-0.094, CI=-0.121;-0.066, p = 1.47×10^-11) and women (β=-0.1065, CI=-0.139;-0.074, p = 1.53×10^-10), with no significant difference in the effects between sexes. The ε2 allele was favorably associated with AD in both men (β=-0.756, CI=-0.865;-0.646, p = 1.41×10^-41) and women (β=-0.805, CI=-0.903;-0.707, p = 2.09×10^-58). There was nether significant difference in the AD effects between sexes nor the ε2 allele was significantly associated with DM (p>0.3).

Genetic susceptibility to both conditions, DM and AD, is more pronounced in men than women. Antagonistic associations the APOE ε4 allele with AD and DM and sex-specific differences in the effects among AD and DM indicate a critical role of heterogeneity in the APOE-related AD-DM risk.