The corpus callosum (CC), which connects the two cerebral hemispheres, is the largest white matter fiber bundle in the human brain. This structure presents a peculiar myelination pattern: it has small diameter fibers, located in the genu, which myelinate much later in normal development, and large diameter fibers of the splenium, which myelinate early in development. Although AD mainly compromise cerebral gray matter structure, there is evidence that white matter may also be involved in the pathology. To illustrate callosal white matter changes in AD pathology, we summarize in vivo MRI imaging studies in humans, focusing on region of interest (ROI), voxel-based morphometry (VBM), diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) techniques. Results from the literature showed that changes in the anterior (genu and anterior body) as well as in the posterior (isthmus and splenum) portions of the CC might already be present in the early stages of AD. The spatial (in anterior and posterior callosal subregions) and the temporal (in the early stage of AD) presence of the CC changes support the hypothesis that two mechanisms, Wallerian degeneration and myelin breakdown, might be responsible for the region-specific changes detected in AD patients. Wallerian degeneration affects the posterior CC subregion, which receives axons directly from those brain areas (temporo-parietal lobe regions) primarily affected by the AD pathology. Instead, the myelin breakdown process affects the later-myelinating CC subregion and explains the earlier involvement of the genu in CC atrophy.