Mutation Lends Support to Amyloid Theory in Alzheimer's Disease

New research confirms the amyloid hypothesis as a major pathophysiologic factor in the development of Alzheimer’s disease.

The discovery of a protein mutation which prevents the neurodegeneration and loss of cognition characteristic of Alzheimer’s disease (AD) provides strong evidence to support the theory that the disease is driven by the accumulation of beta amyloid plaques in the brain.

Researchers from deCODE Genetics, led by Kari Stefansson, MD, chief executive officer of deCODE Genetics, in collaboration with Genentech, searched for low-frequency variants of the amyloid precursor protein (APP) gene associated with AD.

The study, which was published online in the journal Nature, found that a rare mutation in the APP in the DNA of elderly Icelandic individuals protected them from developing AD. The A673T allele, in which alanine is replaced by threonine at position 673, was present in fewer than 1% of the 1795 Icelanders analyzed in the study—but the mutation was 5 times more common in individuals 85 and older who did not have AD compared with those who had been diagnosed with the condition.

Individuals with the APP variant also appeared to have 40% fewer plaque-forming proteins than those with Alzheimer’s. According to the researchers, the APP variant appeared to have the opposite effect of those caused by the mutation in AD—instead of an increased amount of beta amyloid in the brain, the APP variant slowed beta amyloid production.

The protective element of the APP variant was so effective that even individuals displaying risk factors for AD—such as having 2 copies of the gene known as APOE4—did not develop Alzheimer’s.

Many of the drugs currently being developed to treat AD are based on the amyloid theory and the belief that reducing the amount of amyloid in the brain will effectively halt the progression of the disease. Scientists are still trying to evaluate whether the amyloid build-up is the reason for cognitive decline in Alzheimer’s, or is the result of the damage associated with the condition.

The authors claim that their research supports certain AD drug development programs involving beta-secretase (BACE1), “some of which are already in human clinical trials,” according to Dr. Stefansson.

BACE1 is an enzyme involved in the conversion of APP into amyloid beta, which is deposited as plaques in the brains of patients with AD. Many BACE inhibitors—a new class of anti-dementia agents—were showcased at the Alzheimer’s Association International Conference (AAIC) in Vancouver, British Columbia.

“Our findings and the in vitro work done by Genentech also provide a proof of principle for the idea that blocking BACE1 cleavage of APP may protect against Alzheimer‘s, offering greater confidence to pharmaceutical companies with active BACE1 inhibitor drug development programs,” the authors wrote.