Morphologic and functional imaging studies have not always given concordant results about brain areas showing atrophic changes and reduced flow or metabolism in Alzheimer’s disease (AD). The aim of this study was to determine the initial abnormality and the longitudinal changes in both morphologic and functional measurements for the same individuals with AD. We investigated 15 patients with mild AD and 25 age-matched healthy volunteers. The AD patients underwent both MRI and SPECT 3 times at intervals of approximately 1 y. The gray matter volume, as segmented from MRI, and the regional cerebral blood flow (rCBF), as measured by SPECT, of AD patients were compared with those of healthy volunteers using statistical parametric mapping, which is a voxel-based analysis in stereotactic space. Considerable discordance between areas of regional atrophy and areas of decreased rCBF was observed. The medial temporal areas showed a faster and more extensive reduction of gray matter volume than of rCBF. In comparison with the value at the baseline study, rCBF in the posterior cingulate gyrus and precuneus and the associative parietal cortex was extensively decreased. In contrast, the extent of significant decrease in this area continued to be much narrower for gray matter volume than for rCBF, even in the follow-up studies. Frontal areas, including the anterior cingulate gyrus and the orbitofrontal areas, showed a progressive reduction in both rCBF and gray matter volume. The reduction in rCBF was in a more posterior part of the associative temporal cortex than was the reduction in gray matter volume. These results indicate a distinct discordance between morphologic and functional changes in a longitudinal study of AD. Functional changes may be caused partly by remote effects from the morphologically involved areas with decreased connectivity and partly by a compensatory response by neuronal plasticity.