PURPOSE: To investigate the regional changes in gray matter volume by using optimized voxel based morphometry in the whole brain of patients with Alzheimer's disease (AD) and to determine its correlation with cognitive function. MATERIALS AND METHODS: Nineteen patients with AD (mean mini mental state examination (MMSE) score = 20.4) and 19 age-matched control subjects (mean MMSE score = 29) participated in this prospective study. T1-weighted 3D-SPGR scans were obtained for each subject. These T1-weighted images were spatially normalized into study-specific T1 template and segmented into gray matter, white matter and CSF. After the images were modulated and smoothed, all of the gray matter images were compared with control images by using voxel-wise statistical parametric test (two-sample t-test). RESULTS: In patients with AD, total gray matter volume was significantly smaller than normal control (552+/-39 mL vs. 632+/-51 mL, p<0.001). Significant gray matter loss was seen in both the hippocampus and amygdala complexes, and the parahippocampi and frontoparietal cortices (p<0.01, family wise error corrected). Left cerebral atrophy was more prominent than the right. Loss of gray matter volume in both the superior frontal gyri and left inferior temporal gyrus had a strong correlation with lower MMSE score. CONCLUSION: Optimized VBM was able to visualize pathologic changes of AD in vivo. In AD there was widespread gray matter volume loss in the frontoparietal lobes as well as the medial temporal lobes and had a strong correlation between volume loss of specific cortical areas and MMSE score.