Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort

Background Age is the cardinal risk factor for Alzheimer’s disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD. Methods One hundred and seven cognitively unimpaired, late-middle-aged adults from the Wisconsin Registry for Alzheimer’s Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF. Results As expected, there was a significant association between age and WMH ( p < .001). Importantly, there was a significant interaction between age and OUES on WMH ( p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group ( p < .001) but not in the High OUES group ( p = .540), indicating that higher CRF attenuates the deleterious age association with WMH. Conclusions Higher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD.