IntroductionEarly studies have reported that APOE is strongly associated with brain atrophy and cognitive decline among healthy elders and Alzheimer’s disease (AD). However, previous research has not directly outlined the modulation of APOE on the trajectory of cerebral atrophy with aging during the conversion from cognitive normal (CN) to dementia (CN2D).MethodsThis study tried to elucidate this issue from a voxel-wise whole-brain perspective based on 416 qualified participants from a longitudinal OASIS-3 neuroimaging cohort. A voxel-wise linear mixed-effects model was applied for detecting cerebrum regions whose nonlinear atrophic trajectories were driven by AD conversion and to elucidate the effect of APOE variants on the cerebral atrophic trajectories during the process.ResultsWe found that CN2D participants had faster quadratically accelerated atrophy in bilateral hippocampi than persistent CN. Moreover, APOE ε4 carriers had faster-accelerated atrophy in the left hippocampus than ε4 noncarriers in both CN2D and persistent CN, and CN2D ε4 carriers an noncarriers presented a faster atrophic speed than CN ε4 carriers. These findings could be replicated in a sub-sample with a tough match in demographic information.DiscussionOur findings filled the gap that APOE ε4 accelerates hippocampal atrophy and the conversion from normal cognition to dementia.