The etiology of age-related dementia is more complicated than we think.

Alzheimer's disease (AD) is the most common form of age-related dementia (ARD). Most research directed at understanding the causes of AD is focused on the genetic-based pathology associated with the familial form of this disorder. This is important work and significant progress has been made but 85% of all AD patients have the sporadic form of the disorder. This means that a complete understanding of these complex disorders will remain elusive unless alternative approaches are developed. In this paper we want to make two main points. First, we argue that the current diagnostic distinctions between AD and ARD do not accurately reflect the heterogeneity of these disorders. Second, we present an approach to understanding the etiology of these disorders by suggesting that multiple combinations of co-factors produce variants of the sporadic form of AD. Various proof of principle experiments are presented and the mechanistic and treatment implications of this view are discussed. Copyright 2010 Elsevier B.V. All rights reserved.