Associations and interactions between APOE e4 genotype and lifestyle with brain structural phenotypes
Yating You1, Joey Ward1, Frederick K Ho1
1School of Health and Wellbeing, University of Glasgow, Glasgow, Scotland, G12 8TB, United Kingdom.
Brain Communications
|October 27, 2025
Summary
A healthy lifestyle benefits brain health regardless of Alzheimer's risk genes like APOE e4. Unfavorable lifestyles and the APOE e4 gene are linked to poorer brain structure, but their effects are mostly separate, not combined.
Area of Science:
- Neuroscience
- Genetics
- Public Health
Background:
- The Apolipoprotein E (APOE) e4 allele is a significant genetic risk factor for Alzheimer's disease.
- Lifestyle factors (smoking, diet, activity) impact brain health, but their interplay with APOE e4 on brain structure is unclear.
Purpose of the Study:
- To investigate associations and interactions between lifestyle, APOE e4 genotype, and brain structural MRI markers.
- To examine how overall and individual lifestyle factors influence brain volumes and white matter integrity in relation to APOE e4 status.
Main Methods:
- Cross-sectional study using UK Biobank MRI data (N=24,912) of non-demented participants.
- Lifestyle categorized into 'favourable', 'moderate', and 'unfavourable' based on adherence to guidelines.
- Linear regression analyzed associations and interactions of lifestyle levels, APOE e4, and specific factors with brain volumes and white matter integrity (DTI, NODDI).
Main Results:
- Unfavourable lifestyles were independently associated with smaller grey matter, hippocampus, and total brain volumes.
- APOE e4 presence linked to smaller hippocampal volumes and reduced white matter integrity.
- Individual unhealthy factors like smoking and high alcohol intake correlated with poorer brain structural markers.
- Interactions between lifestyle levels and APOE e4 status on brain metrics were generally non-significant.
Conclusions:
- Both APOE e4 and non-favourable lifestyles are associated with worse brain health, primarily through linear, non-synergistic effects.
- The positive impact of a healthy lifestyle on brain structure is consistent across different genetic risk profiles for dementia.
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