What Causes AD? The Amyloid Hypothesis

Contributed by: Michael Rafii, M.D., Ph.D - Director of the Memory Disorders Clinic at the University of California, San Diego.

This is the second blog in my series about causes of AD.

Among many theories about the complex cause of Alzheimer’s disease, the amyloid hypothesis is currently driving the most drug development. The amyloid hypothesis states that a buildup of deposits (amyloid) is the fundamental cause of Alzheimer’s disease. It is a compelling theory because a gene associated with this form of amyloid is located on chromosome 21 and people with an extra copy of this gene (those with Down Syndrome) almost universally exhibit AD by 40 years of age.

Also, APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, amyloid buildup precedes clinical AD. Further evidence comes from the finding that mice with a mutant form of the human genes associated with amyloid develop Alzheimer's-like brain pathology.

Evidence that potentially weakens this theory is that an experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.

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