Associations between lifestyle, genetic risk for Alzheimer's disease, and longitudinal brain atrophy in UK Biobank (N=2214)

INTRODUCTION: Modifiable behaviours such as smoking, diet, alcohol intake, sedentariness, and physical inactivity are associated with brain health, but longitudinal evidence in adults without dementia is limited.METHODS: Among 2214 UK Biobank participants with two MRI scans over 2.2 years, unweighted lifestyle scores (ranging 0 - 10) were derived from five behaviours and classified as unfavourable, moderate, or favourable. Linear regression examined associations, and APOE e4 genotypic interactions, with changes in 16 brain volumetric markers.RESULTS: Compared with favourable lifestyle, unfavourable lifestyle showed significantly greater grey matter (2059 mm³; 0.046 standard deviations [SDs]) and left hippocampal (36.5 mm³; 0.044 SD) atrophy. Moderate-risk drinking was linked to higher total brain atrophy (2075 mm³; 0.063 SD), while high-risk drinking and low physical activity associated with accelerated regional grey matter loss. No effects were found for smoking, diet, or sedentariness. High-risk drinking was associated with greater frontal lobe atrophy, particularly among APOE ε4 carriers.DISCUSSION: Lifestyle variables showed modest associations with brain atrophy, with alcohol drinking appearing most influential, with significant modification by APOE e4 genotype.