INTRODUCTION: Understanding disease progression in Alzheimer's disease (AD) awaits the resolution of three fundamental questions: first, can we identify the location of "seed" regions where neuropathology is first present? Some studies have suggested the medial temporal lobe while others have suggested the hippocampus. Second, are there similar atrophy rates within affected regions in AD? Third, is there evidence of causality relationships between different affected regions in AD progression? METHODS: To address these questions, we conducted a longitudinal MRI study to investigate the gray matter (GM) changes in AD progression. Abnormal brain regions were localized by a standard voxel-based morphometry method, and the absolute atrophy rate in these regions was calculated using a robust regression method. Primary foci of atrophy were identified in the hippocampus and middle temporal gyrus (MTG). A model based upon the Granger causality approach was developed to investigate the cause-effect relationship over time between these regions based on GM concentration. RESULTS: Results show that in the earlier stages of AD, primary pathological foci are in the hippocampus and entorhinal cortex. Subsequently, atrophy appears to subsume the MTG. CONCLUSION: The causality results show that there is in fact little difference between AD and age-matched healthy control in terms of hippocampus atrophy, but there are larger differences in MTG, suggesting that local pathology in MTG is the predominant progressive abnormality during intermediate stages of AD development.