APOE ε4 hastens age-related brain shrinkage in older adults without dementia

Published on May 30, 2023

Imagine your brain as a house that’s slowly shrinking over time. Well, researchers have discovered that a specific gene, APOE ε4, acts like a turbocharger on this process of cerebral atrophy. This study aimed to uncover how APOE variants impact the trajectory of brain shrinkage from normal cognition to dementia. Using brain imaging data from over 400 participants, they found that individuals with dementia had a faster decline in the size of their hippocampi compared to those with normal cognition. Additionally, APOE ε4 carriers experienced even more rapid shrinkage in the left hippocampus, regardless of whether they had dementia or not. Furthermore, these effects were seen in both groups of participants who carried the ε4 variant and those who didn’t, but were more pronounced in those with dementia. These findings were also confirmed in a separate group of participants who closely matched the demographic characteristics of the original sample. This study sheds light on how APOE ε4 influences hippocampal atrophy and the onset of dementia.

Early 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). This 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. We 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. Our findings filled the gap that APOE ε4 accelerates hippocampal atrophy and the conversion from normal cognition to dementia.

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