Nonlinear interaction between APOE ε 4 allele load and age in the hippocampal surface of cognitively intact individuals

Abstract The ε 4 allele of the gene Apolipoprotein E is the major genetic risk factor for Alzheimer's Disease. APOE ε 4 has been associated with changes in brain structure in cognitively impaired and unimpaired subjects, including atrophy of the hippocampus, which is one of the brain structures that is early affected by AD. In this work we analyzed the impact of APOE ε 4 gene dose and its association with age, on hippocampal shape assessed with multivariate surface analysis, in a ε 4 ‐enriched cohort of n = 479 cognitively healthy individuals. Furthermore, we sought to replicate our findings on an independent dataset of n = 969 individuals covering the entire AD spectrum. We segmented the hippocampus of the subjects with a multi‐atlas‐based approach, obtaining high‐dimensional meshes that can be analyzed in a multivariate way. We analyzed the effects of different factors including APOE, sex, and age (in both cohorts) as well as clinical diagnosis on the local 3D hippocampal surface changes. We found specific regions on the hippocampal surface where the effect is modulated by significant APOE ε 4 linear and quadratic interactions with age. We compared between APOE and diagnosis effects from both cohorts, finding similarities between APOE ε 4 and AD effects on specific regions, and suggesting that age may modulate the effect of APOE ε 4 and AD in a similar way.