Effects of aerobic exercise and cardiorespiratory fitness on white matter free water fraction in older adults: a 1-year randomized controlled trial.

Free water fraction (FWF), derived from diffusion MRI, is a sensitive biomarker of white matter microstructure and may be modifiable through lifestyle interventions. The mid-anterior corpus callosum (CC) has been proposed as particularly responsive to physical exercise and the related increases in cardiorespiratory fitness. This study examined the effects of aerobic exercise training and fitness on FWF in the CC and on cognitive performance in older adults. Seventy-three participants (mean age 69 ± 5 years, 77% women) were randomized to a 1-year aerobic training or stretching intervention. FWF was assessed using diffusion tensor MRI, fitness via maximal oxygen uptake (VO2max), and cognition using a composite score of reasoning, memory, and processing speed. Linear mixed models revealed a significant increase in VO2max following aerobic training compared to stretching, while cognitive performance improved in both groups. A significant region × group × time interaction was observed for FWF, although Bonferroni-corrected pairwise comparisons showed no significant group difference. However, complete-case analysis of the mid-anterior CC showed a significant FWF reduction in the CC body following aerobic training compared to stretching (- 2.71 ± 5.44% vs. 0.63 ± 6.42%, p = 0.048). Tract-based spatial statistics indicated that lower baseline VO2max predicted greater FWF increases in the CC body and genu across groups. Baseline FWF was negatively correlated with cognitive performance. These findings suggest that 1 year of aerobic training may reduce FWF in the CC body and that higher physical fitness preserves white matter microstructure and support cognitive health in older adults.