Amyloid plaques and neurofibrillary tangles are the hallmarks of Alzheimer's disease and have been the focus of disease etiology and pathogenesis. However, in the larger picture of a complex disease, the precise etiology of the lesions per se, as well as the clinical disease, remain to be defined. In this regard, to date no single process has been identified as a useful target and treatment efforts have shown no meaningful progress. Therefore, alternative ideas that may lead to new and effective treatment options are much needed.