Testing the structural disconnection hypothesis: Myelin content correlates with memory in healthy aging

Abstract

Introduction: The “structural disconnection” hypothesis of cognitive aging suggests that deterioration of white matter (WM), especially myelin, results in cognitive decline, yet in vivo evidence is inconclusive. Methods: We examined age differences in WM microstructure using Myelin Water Imaging and Diffusion Tensor Imaging in 141 healthy participants (age 20–79). We used the Virginia Cognitive Aging Project and the NIH Toolbox® to generate composites for memory, processing speed, and executive function. Results: Voxel-wise analyses showed that lower myelin water fraction (MWF), predominantly in prefrontal WM, genu of the corpus callosum, and posterior limb of the internal capsule was associated with reduced memory performance after controlling for age, sex, and education. In structural equation modeling, MWF in the prefrontal white matter and genu of the corpus callosum significantly mediated the effect of age on memory, whereas fractional anisotropy (FA) did not. Discussion: Our findings support the disconnection hypothesis, showing that myelin decline contributes to age-related memory loss and opens avenues for interventions targeting myelin health.