OBJECTIVE: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects the corpus callosum (CC), which plays a key role in interhemispheric coupling in high-demand conditions. Using 3D callosal measurements and a letter-matching paradigm, this 2-part study investigated the neural substrate of interhemispheric coupling in individuals with AD or amnestic mild cognitive impairment (a-MCI) and age-matched healthy individuals (HC). METHOD: Thirty-three right-handed participants were MRI scanned to measure the volume of the CC in 5 sections. In Study 1, AD, a-MCI, and HC individuals performed a low-demand perceptual letter shape-matching task (e.g., A-A); in Study 2, a-MCI and HC individuals performed a “case-sensitive” letter-matching task (Study 2A) and a “load-sensitive” letter-matching task (Study 2B). RESULTS: The results showed a positive correlation between Response Times and the midbody of the CC at the lowest cognitive demand level (Study 1) in participants with AD, and the total CC, midbody, caudal body, and isthmus of the CC at high cognitive demand levels (Study 2A) in normal aging. The volume of the anterior part of the CC was significantly negatively correlated with the interhemispheric behavioral indices for the a-MCI group (Study 1 and Study 2B). CONCLUSION: This study provides evidence that interhemispheric coupling may constitute a flexible mechanism that can improve the brain’s ability to meet processing demands for low cognitive demand in AD and for high cognitive demand in normal aging.