Sex modifies the APOE-related risk of developing Alzheimer disease

Abstract

Objective: The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.

Methods: Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative.

Results: Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women).

Interpretation: APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis.

Figure 1. The APOE4 carrier status increases the risk of clinical decline in healthy older women, but not men

The main figure shows the survival function plot for conversions from healthy control to either MCI or possible/probable AD based on left-truncated and right-censored data. In contrast to the Cox regression no stratification or covariate adjustment was applied. Subjects younger than 55 years were excluded (N=211; 3.8%) from the plot for visualization purposes only; the Cox model featured all available subjects. The inset depicts the hazards ratio for converting from HC to MCI or AD computed separately for each sex using a Cox regression model (* and *** signify significant effects with P≤0.5 and P<0.001, respectively). Blue and red refer to males and females, respectively.

Figure 2. The APOE4 carrier status increases the risk of clinical decline in women with MCI more than in men

The main figure shows the survival function plot for conversions from MCI to possible/probable AD based on left-truncated and right-censored data. In contrast to the Cox regression no stratification or covariate adjustment was applied. Subjects younger than 55 years were excluded (N=71; 2.7%) from the plot for visualization purposes only; the Cox model featured all available subjects. The inset depicts the hazards ratio for converting from MCI to AD computed separately for each sex using a Cox regression model (*** signifies a significant effect with P<0.001). Blue and red refer to males and females, respectively.

Figure 3. Sex modifies the APOE4 effect on spinal fluid biomarker levels

CSF biomarker levels in HCs and MCI subjects are shown with 95% CI. Depicted CSF Biomarker levels were adjusted for age, age-squared, years of education, MMSE score and ADNI study phase. Blue squares and red circles correspond to men and women, respectively. Dashed lines highlight the change in CSF levels between ε3 homozygotes and ε4 heterozygotes. P-values for the APOE by sex effect were computed using an ANCOVA. *: P<0.05 (corrected for multiple comparisons) **: P<0.01 (corrected). Subfigures a, b, c, and d correspond to Abeta, total tau, tau-to-Abeta-ratio, and p-tau, respectively.