Associations Between Walking Pace, APOE-ϵ4 Genotype, and Brain Health in Middle-Aged to Older Adults

Poor physical function and possession of the e4 allele of the apolipoprotein E (APOE) gene are each associated with increased dementia risk, but it is unclear how these exposures interact to influence brain health. Purpose This study aimed to investigate whether self-reported walking pace (a marker of physical function) and the presence of APOE-ϵ4 allele interact to modify brain health outcomes. Methods We used data from a prospective cohort study of middle-aged to older adults from the UK Biobank who self-reported walking pace (slow or steady-to-brisk) and who were initially free of dementia (n = 415,110). Incident all-cause dementia was obtained from hospital and death registry records, and structural brain volumes (right and left hippocampus volumes, total gray matter volume, and volume of white matter hyperintensities) were measured from a subset of participants (n = 33,113). Cox proportional hazard models and generalized linear models were used to assess associations between exposures and outcomes. Results Slow walking pace and the presence of APOE-ϵ4 allele were associated with increased dementia risk (HR = 1.79 [95% CI = 1.66-1.93], P < 0.001; HR = 3.06 [2.90-3.23], P < 0.001, respectively), and there was an interaction between these associations, indicating that the association of walking pace with dementia risk is modified by APOE-ϵ4 status (reference group: HR_{Steady-Brisk/APOE-ϵ4-} = 1; HR_{Slow/APOE-ϵ4-} = 2.03 [1.84-2.25], P < 0.001; HR_{Steady-Brisk/APOE-ϵ4+} = 3.21 [3.02-3.41], P < 0.001; HR_{Slow/APOE-ϵ4+} = 4.99 [4.48-5.58], P < 0.001). Slow self-reported walking pace was associated with worse brain volume outcomes, and these associations were not modified by APOE-ϵ4 genotype. Conclusions These results suggest walking pace and APOE-ϵ4 status independently influence brain volume outcomes, but both factors independently and jointly contribute to increased dementia risk. Individuals with both risk factors (slow walking pace and APOE-ϵ4 allele) show the strongest associations with dementia risk.