Deleterious network hypothesis of Alzheimer's disease.

Numerous studies indicate that aberrant amyloid precursor protein metabolism, elevated peroxidative damage, depressed energy metabolism and altered calcium homeostasis are four pivotal deleterious factors in the pathogenesis of Alzheimer's disease. Cumulative evidence further suggests that these four factors are intimately interrelated, forming a deleterious network. Based on this new concept of 'deleterious network', a unifying hypothesis-the deleterious network hypothesis of Alzheimer's disease-is proposed. The main ideas of the hypothesis are delineated as follows: increases in free radical damage, alterations in amyloid precursor protein metabolism, impairment of energy metabolism and abnormalities of calcium homeostasis are four cornerstones of a deleterious network. Various risk factors of Alzheimer's disease can triger the network by promoting the occurrence of one of these key components, resulting in the biological abnormalities of Alzheimer's disease. Based on this new theory, a majority of the important observations about Alzheimer's disease can be explained consistently and succinctly.