Alzheimer's disease (AD) is clinically characterized as a progressive dementia starting with memory dysfunction and characterized pathologically as neurodegeneration accompanied by deposition of amyloid-beta, neurofibrillary tangles, and neuronal loss. AD research has endeavored to explain the clinical symptoms of AD through pathological changes and to develop various therapies for AD. Fulfillment of these goals, however, remains on the horizon. In this article, I review the relationship between neuropathological changes that occur in the brain and clinical progression of AD, and propose a hypothesis that brain aging, characterized by neurofibrillary tangles in entorhinal cortex, is pre-requisite for development of AD.