Submitted by cordis on Fri, 13/03/2009 - 10:22am
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De Fede. G et al. (2009) A recessive mutation in the APP gene with dominant-negative effect on amlyoidogensesis. Science 323: 1473-1477. DOI: 10.1126/science.1168979.
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EU-funded researchers have discovered a new genetic mutation that causes Alzheimer's disease in people who inherit it from both parents. Interestingly, people who inherit one copy of the mutated gene from one parent (along with a healthy version of the gene from their other parent) appear to enjoy increased protection against the condition.
The findings, published in the journal Science, could lead to new treatments for Alzheimer's and could also have implications for the genetic screening of families with a history of the disease. EU support for the study came from the NEURON ('Network of European funding for neuroscience research') initiative, which is funded under the 'Coordination of research activities' budget line of the Sixth Framework Programme (FP6).
Alzheimer's disease is one of the most common forms of dementia in the elderly. It is characterised by the build up in the brain of plaques made of beta amyloid protein fragments; these fragments come from a bigger protein called the amyloid precursor protein, or APP. Sufferers gradually lose their ability to think, remember, reason and communicate, and those in the most advanced stages of the disease are entirely reliant on others for their care. As yet, there is no cure for Alzheimer's disease.
Although just a tiny percentage of Alzheimer's cases are inherited, not only do people in this category tend to develop the disease early on in life but the condition also progresses more rapidly than normal cases. A number of mutations linked to early-onset Alzheimer's have been identified, all of which are located in the gene responsible for producing the amyloid precursor protein (or APP), or the presenilin 1 and presenilin 2 genes.
All these mutations are dominant, which means that people with just one copy of the mutation will develop Alzheimer's, even if they also have a healthy version of the gene as well.
In contrast, the newly discovered genetic mutation is recessive, which means that people will not develop the disease unless they have inherited two copies of the mutation. The mutation was picked up in a patient with early-onset dementia who first went to his doctor complaining of behavioural and cognitive problems at the age of 36. The patient's condition continued to decline, and within eight years, he needed full-time care. The patient's younger sister also has a mild cognitive impairment.
Analyses of the mutation revealed that it both leads to enhanced amyloid-beta production and boosts the tendency of the amyloid beta to clump together in plaques.
However, in patients with one healthy and one mutated copy of the gene, the normal protein and mutated protein interacted in such a way that plaque formation was effectively blocked. This finding is in line with the discovery that, even in old age, people carrying just one mutated copy of the gene remain Alzheimer's free.
According to the researchers, the findings highlight the importance of screening for those both with and without dementia for mutations in the APP gene. They note that genetic variants currently thought to be harmless may turn out to cause disease in individuals with two copies of that variant.
The researchers conclude: 'The identification of such mutations would help to prevent the occurrence of the disease in their carriers.'