Associations Between Walking Pace, APOE Genotype, And Brain Health In Middle-aged To Older Adults

Poor physical function and possessing the ε4 allele of the apolipoprotein E (APOE) gene are each associated with increased risk of dementia, but it is unclear how these exposures interact to influence brain health. PURPOSE: To investigate whether self-reported walking pace (a marker of physical function) and the presence of the APOE-ε4 allele interact to modify brain health. METHODS: We used data from a prospective study of middle-aged to older adults from the UK Biobank who self-reported walking pace (slow or steady-to-brisk) and were initially free of dementia (n = 415,110). Incident all-cause dementia was obtained from hospital records and death registries, and structural brain volumes (right and left hippocampus [RH; LH], total gray matter volume [GMV], and white matter hyperintensities [WMH]) 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. Models were adjusted for total intracranial volume, age, sex, education, BMI, Townsend Deprivation Index, chronic diseases, depression, smoking, alcohol, and healthy diet. RESULTS: Slow walking pace was associated with increased risk of dementia [HR = 1.79 (1.66,1.93), p < 0.001] and this association was modified by APOE-ε4 status [HRwp x APOE = 0.76 (0.66, 0.88), p < 0.001], such that regardless of walking pace, individuals who possess the APOE-ε4 allele had a greater risk for dementia compared with individuals without the APOE-ε4 allele [(reference group: HRSteady-Brisk/APOE-ε4- = 1); HRSlow/APOE-ε4- = 2.03(1.84, 2.25), p < 0.001; HRSteady-Brisk/APOE-ε4+ = 3.21(3.02, 3.41), p < 0.001; HRSlow/APOE-ε4+ = 4.99 (4.48, 5.58), p < 0.001]. Slow self-reported walking pace was associated with worse brain volume outcomes [GMV: β = -3243.02 (-4878.91, -1607.14), p < 0.001; RH: β = -27.29 (-48.10, -6.47), p = 0.03; LH: β = -22.73 ( -43.23, -2.23), p = 0.032; WMH: β = 0.14 (0.08, 0.20), p < 0.001] and these associations were not modified by APOE-ε4 genotype. In sensitivity analyses that accounted for physical activity levels and disability, relationships remained significant for dementia, GMV, and WMH. CONCLUSION: These findings highlight the importance of assessing both physical function and APOE genotype when evaluating brain health. This work was supported by the National Institutes of Health (P30AG072980, P30AG019610, R56AG067200, R01AG049464, R01AG072445), the state of Arizona and Arizona Department of Health Services, and the McKnight Brain Research Foundation.