Associations and interactions between <i>APOE</i> e4 genotype and lifestyle with brain structural phenotypes

Apolipoprotein <i>E</i> gene (<i>APOE</i>) e4 allele is known as the strongest common genetic risk factor for Alzheimer's disease. Various lifestyle factors are reported to have multiple associations with brain health, including smoking, alcohol intake, diet, sedentary behaviour and physical activity. However, the associations and interactions of overall or individual modifiable lifestyle factors and <i>APOE</i> e4 genotype, on brain volumes and white matter tract integrity measured by diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI), remain incompletely understood. In this cross-sectional study, we used data from the UK Biobank MRI assessment (<i>N</i> = 24 912) participants living without dementia. They were classified as having 'favourable', 'moderate' and 'unfavourable' levels based on their lifestyle scores (0-10 points) being calculated by the magnitudes of adherence to five healthy lifestyle guidelines: two points for each healthy category, one point for moderate ones, and zero point for unhealthy ones. Neuroimaging markers, namely brain volumes and white matter tract integrity measures, were derived from MRI. Linear regression was performed to examine the associations and interactions of lifestyle levels, <i>APOE</i> e4 genotype and each lifestyle factor, with multiple brain structural MRI phenotypes. We found that compared with favourable-level lifestyle, moderate and unfavourable levels were significantly independently associated with smaller grey matter, hippocampus and total brain volumes (standardized β range 0.004-0.096 per unit). Significant associations were found between <i>APOE</i> e4 presence and smaller hippocampal volumes (β range 0.042-0.048 lower versus absence) and worse white matter tract integrity. Individual unhealthy lifestyle aspects were mostly associated with poorer brain structural markers, such as current smoking (β range -0.014 to 0.209), high-level drinking (β range -0.105 to 0.152) and grey matter and white matter, as well as both traditional white matter tract and NODDI metrics, in both individually and simultaneously modelled lifestyle-factor models. The interactions between lifestyle levels and <i>APOE</i> e4 status on brain metrics were generally non-significant. In conclusion, the presence of <i>APOE</i> e4 and non-favourable lifestyles were mostly associated with worse brain health, and this was largely linear rather than synergistic. The benefit of a healthy lifestyle on brain health does not vary by genetic risk for dementia.