The brain circuit pathways of major depressive disorder (MDD) and Alzheimer’s disease (AD) could overlap. The authors hypothesized that AD and MDD subjects would have different diffusion parameters compared to healthy elderly controls (HE). Forty-seven age-matched subjects (AD=19, MDD=11, HE=20) were enrolled and performed MRI included structural brain imaging and diffusion kurtosis imaging (DKI) and then diffusional parameters were compared to differentiate between the three groups. Caudate nucleus and thalamus revealed significant different of diffusion parameters between AD and HE, and between AD and MDD but no significant different between MDD and HE. Diffusion imaging can demonstrate microstructural change in AD.