Next, to determine the age at which total hippocampal volumes of those with ε2/ε3, ε3/ε4, and ε4/ε4 diverge from that of ε3/ε3 carriers, we modeled its association with age for each APOE genotype using a generalized additive model (GAM) with a cubic regression spline using the “mgcv” R package (version 1.9). 27 Pairwise differences between fitted smooths were then estimated and the point at which ε2/ε3, ε3/ε4, and ε4/ε4 diverged from ε3/ε3 was defined as the age when the confidence intervals no longer overlapped.
