P1–256: APOE genotype by gender interaction revealed in CSF biomarkers and clinical conversion rates in the ADNI database

The influence of the APOE genotype on the risk of developing AD is well characterized. However, the fact that APOE4-carrying women are at higher risk of developing AD than their male counterparts is not as well known. Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database we studied the interaction between APOE genotype and gender in two domains: (i) CSF biomarker levels and (ii) conversion rates from healthy control to either MCI or AD. All data originate from the ADNI database and subjects were either APOE3 homozygotes (APOE3/3) or APOE3/4 heterozygotes. CSF biomarker levels (Aβ, Tau, and Tau/Aβ-ratio) were studied separately in healthy controls (N=180) and MCI patients (N=366). The APOE-by-gender interaction was examined using an ANCOVA adjusting for APOE, gender, age, years of education, and ADNI study phase. For studying conversion rates we analyzed 194 healthy controls who had at least 12 months of follow-up at time of analysis. During the observation period 35 subjects converted to MCI or AD. Conversion rates were modeled using a left-truncated, right-censored Cox proportional hazards model with APOE, gender, and APOE-by-gender interaction as covariates. The analysis is stratified by education and MMSE at baseline. In healthy controls, the APOE-by-gender interaction was only significant for the Aβ levels (p=.022) reflecting higher levels in APOE3/3 men and a more pronounced reduction in APOE3/4 heterozygous men. In the MCI group, the APOE-by-gender interaction was significant for Tau (p=0.013) and the Tau/Aβ-ratio (p=0.042), but not for Aβ (p=0.49). Here, the increase in Tau and in the Tau/Aβ-ratio between APOE3/3 and APOE3/4 subjects was more pronounced in women (Figure 1). In the Cox model, all three coefficients were significant (APOE: p<.006; gender: p=.01; APOE-by-gender interaction: p=.017). Corresponding hazard ratios are listed in Table 1. Although sample sizes are limited, Aβ levels in controls suggest increased vulnerability in APOE4-carrying men, and tau levels in MCI patients suggest increased vulnerability in APOE4-carrying women. In the most relevant outcome, clinical conversion, the APOE4 effect is more potent in women. These results support a pathogenic model in which the APOE4 allele lowers beta-amyloid levels in both genders but has additional downstream effects in women. Average CSF biomarker level in healthy controls (A) and MCI patients (B). The control group comprises 71 APOE3/3 men, 66 APOE3/3 women, 24 APOE3/4 men, and 19 APOE3/4 women. The MCI group comprises 124 APOE3/3 men, 77 APOE3/3 women, 91 APOE3/4 men, and 72 APOE3/4 women. Pairwise P-values for each group comparison are depicted on top. Panels (1), (2), and (3) correspond to Abeta, Tau, and Tau/Abeta ratio, respectively.