Associations between lifestyle, genetic risk for Alzheimer's disease, and longitudinal brain atrophy in UK Biobank (N=3224)

Background and Objectives: Modifiable lifestyle behaviours associated with brain health include smoking, diet, alcohol intake, sedentary behaviour and physical inactivity. However, longitudinal evidence on their contributions to structural brain atrophy, considering APOE e4 risk, in populations living without dementia remains scarce. Methods: In the UK Biobank, lifestyle scores were calculated based on the above five lifestyle behaviours at initial MRI assessment. Participants were classified into unfavourable (0-3 ‘points’), moderate (4-6) and favourable (7-10) lifestyle groups. Structural change phenotypes were calculated from two brain MRI assessments over the median follow-up of 2.3 years (up to seven years). Linear regression models were applied to estimate associations between lifestyle and structural changes in 15 brain imaging markers, and their potential interactions with APOE e4 genotype. Results: Among 3224 participants living without dementia who underwent two scans (median follow-up = 2.25 years), unfavourable lifestyle was associated with 28.9 mm3 greater atrophy in the left hippocampus, equivalent to 0.041 standard deviations (SD) greater loss (P=0.048; versus ‘favourable’). APOE e4 carriers showed 24.7 mm3 greater left hippocampal atrophy (0.049 SDs, p(FDR)=0.030) and 195.3 mm3 greater grey matter loss in the frontal pole (0.050 SD, p(FDR)=0.030) versus non-carriers. Compared with high levels of physical activity, low (unstandardised beta=0.049, 0.038 SDs, P=0.038) and medium (unstandardised beta=0.054, 0.043 SDs, P=0.022) levels showed greater increase in white matter hyperintensities (WMH) volumes. No interactions were observed between lifestyle and APOE e4 on brain atrophy.Discussion: Lifestyle and genetic risk contribute to longitudinal brain atrophy, with unfavourable lifestyle, specifically less physical activity, and APOE e4 associated with greater hippocampal atrophy and WMH burden. Promoting a healthy lifestyle, particularly more physical activity, may help slow brain structural decline and delay cognitive ageing regardless of genetic risk.