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Amyloid Cascade Hypothesis of Alzheimer's Disease

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Updated March 05, 2011

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Many researchers believe that the amyloid cascade hypothesis best explains the cause of Alzheimer's disease.

While many questions are still unanswered, the amyloid cascade hypothesis proposes that excessive accumulation of a peptide called amyloid-beta is the key event in Alzheimer's disease: This accumulation sets off a series of events that results in the death of brain cells, and eventually, Alzheimer's disease.

Amyloid-beta is formed from a large protein called amyloid precursor protein (APP). Researchers don't exactly know the function of APP yet, but it may impact the activity of brain cells. Special enzymes (called secretases) cut this protein at specific sites, and one of the products of this "cleavage" is the amyloid-beta peptide. These amyloid-beta peptides clump together into what's called oligomers, and according to the amyloid cascade hypothesis, it is these oligomers that are toxic to brain cells, causing the very early cognitive problems in Alzheimer's disease. Later, these oligomers form the plaques that are characteristic of Alzheimer's disease, but it is the oligomers -- as opposed to the plaques -- that are the actual toxic agents.

While several lines of evidence that support the amyloid cascade hypothesis, there are also a number of challenges to it. For one thing, the amyloid-beta that accumulates in plaques occurs in normal aging as well as Alzheimer's disease. For another, deposits of another protein called tau form tangles that correlate better with cognitive problems in Alzheimer's disease than do plaques. Finally, there are other alternative theories, such as the mitochondrial cascade hypothesis, that have been proposed as explanations of what causes Alzheimer's disease.

Source:

Christensen DD. Alzheimer’s disease: progress in the development of anti-amyloid disease- modifying therapies. CNS Spectr. 2007;12:113-123.

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