Testing for associations and interactions between APOE e4 genotype and lifestyle, with brain structural imaging phenotypes in UK Biobank

Apolipoprotein E gene ( APOE ) e4 allele is the strongest common genetic risk factor for dementia. High genetic risk of dementia could be offset by healthy lifestyle. However, the effects of daily lifestyle and genetic risk on brain structural imaging phenotypes, including white matter (WM) tract integrity, remain unclear. Multiple linear regression and interaction analyses were performed to examine the associations between APOE e4 genotype and lifestyle factors (smoking, alcohol drinking, diet, physical activity, and sedentariness) with 14 brain health metrics among N = 24,912 non-demented participants from UK Biobank, including after adjustment for potential confounders. There were significant associations between APOE e4 presence and smaller hippocampal volume (standardised β range 0.042 to 0.048 versus absence), and multiple metrics of worse WM tract integrity. Compared with participants with favourable lifestyles, moderate and unfavourable lifestyles showed smaller grey matter, total brain, and hippocampal volumes (standardised β range 0.004 to 0.096) per one-unit worse lifestyle significantly. The unhealthiest lifestyle factors were mostly associated with poorer brain health. A 1-point better lifestyle score was associated with better brain health (standardised β range 0.001 to 0.017 per unit). The interactions between lifestyle levels and APOE e4 status on brain metrics were generally non-significant. The presence of APOE e4 and unfavourable lifestyle were mostly associated with worse brain health, and this was largely linear rather than synergistic. The benefit of healthy lifestyle on brain health does not vary by genetic risk for dementia. These findings warrant additional large-scale longitudinal studies to confirm and investigate associations across more brain structural phenotypes.