Abstract
Abstract only Alterations in white matter microstructure (WMM) are associated with reduced cognitive function in patients with Alzheimer’s disease and related dementias, especially of vascular origin. Cardiorespiratory fitness (CRF) and habitual exercise can positively influence brain health; however, the impact on WMM is not clear. The purpose of our study was to assess the relationship between CRF and habitual exercise participation on WMM in healthy older adults. We hypothesized that CRF and habitual exercise would be positively associated with WMM in tracts more susceptible to age-related change or those related to motor function. Older adults free of underlying disease participated in this study (n=23, age=64±5 yrs, M=12, F=11). CRF was assessed using an incremental maximal exercise test on a cycle ergometer (VO2max) and habitual exercise was assessed using the Godin Leisure-Time Exercise Questionnaire (Godin Score). On a separate visit, WMM was measured using neurite orientation dispersion and density imaging (NODDI) MRI scans. Neurite density index (NDI), fraction of isotropic diffusion compartment (FISO), and orientation dispersion index (ODI) were analyzed in twenty-seven white matter tracts defined by the Johns Hopkins Atlas. Associations between VO2max, Godin scores, and WMM in each white matter tract were evaluated using multivariable linear regression while controlling for age and sex. VO2max was a significant predictor of ODI in the genu of the corpus callosum (β=0.714, B=0.001, 95% CI [0.000, 0.002], p=0.007), corticospinal tract (β=0.553, B=0.003, 95% CI [0.000, 0.006], p=0.035), inferior cerebellar peduncle (β=0.558, B=0.001, 95% CI [0.000, 0.003], p=0.024), cerebral peduncle (β=0.566, B=0.001, 95% CI [0.000, 0.002], p=0.040), and uncinate fasciculus (β=0.607, B=0.001, 95% CI [0.000, 0.002], p=0.023). Godin scores significantly predicted ODI in the medial lemniscus (β=0.448, B=0.001, 95% CI [0.000, 0.001], p=0.033). VO2max also significantly predicted FISO of the sagittal striatum (β=0.519, B=0.002, 95% CI [0.000, 0.004], p=0.031). Neither VO2max nor Godin scores were significantly associated with NDI in any of the white matter tracts (p >0.05). Notably, after applying a Benjamini-Hochberg FDR correction for multiple comparisons (q=0.05), neither VO2max nor Godin scores were significantly associated with any WMM variables in any of the white matter tracts. In conclusion, cardiorespiratory fitness was associated with white matter microstructure, especially the orientation dispersion index, in several tracts associated with aging and motor function. However, the significance of these associations depended on the analytical approach. Future studies should examine longitudinal relationships between cardiorespiratory fitness and white matter microstructure to better understand the role of habitual exercise in mitigating risk for Alzheimer’s disease and related dementias. Funding: National Institutes of Health - HL118154 (JNB), HL007936 (KBM) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.