Although a vast number of experimental investigations have focused on various aspects of Alzheimer’s disease (AD), the pathogenic mechanism of the disease has not been established. AD research is a dynamically changing field that has entertained a variety of hypotheses. Since most of the data pertaining to AD pathogenesis is obtained in postmortem tissue or in vitro experiments, researchers must play a game of ‘connect the dots’ to try to correlate the diverse aspects of the disease and generate hypotheses regarding the sequence of pathological events. This article reviews the current state of AD research, and presents three hypothetical models for disease progre