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Rare Gene Mutation Could Galvanize Alzheimer's Research

Posted Jul 12 2012 10:53am


The genetic data indicate that the mutation is protective against Alzheimer‘s disease. This also provides a proof of principle for the idea that blocking BACE1 cleavage of APP may protect against Alzheimer‘s, offering greater confidence to pharmaceutical companies; and subsequently, increase funding for drug development programs for the treatment of Alzheimer's.

Alzheimer's Reading Room

Dr. Kári Stefánsson
deCODE Genetics

From the Cure Alzheimer's Fund
"On Wednesday, scientists announced a finding, published in the journal Nature, that a single gene which causes the rare, early-onset form of Alzheimer’s disease can also carry a mutation that serves to protect against the disease.

This mutation blocks the build-up of excess beta amyloid, and shows that beta amyloid is "the prime therapeutic target" says Rudy Tanzi, Chair of the Cure Alzheimer’s Fund Research Consortium.
Cure Alzheimer’s funded researcher Sam Gandy called the finding “extraordinarily important, the most significant in the field since researchers first reported a mutation that leads to the disease, 22 years ago. "These findings support drug development to modulate the amount of beta amyloid in the brain as a preventative for Alzheimer’s disease".
The good news here is that this research supports the beta amyloid theory and might be the catalyst for more sizable research funding to "hasten" the search for an effective treatment.

Forget about getting tested for the gene, it is so rare it would not be worth it.

Continue reading about the deCODE Genetics discovery below.


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deCODE Genetics Discovers Mutation Conferring Protection Against Alzheimer’s Disease and Cognitive Decline in Elderly

• Study Indicates Link Between Age-Related Cognitive Decline and Alzheimer’s Disease
• Results Support Drug Development of BACE1 Inhibitors for Alzheimer’s Disease

deCODE Genetics, a global leader in analyzing and understanding the human genome, together with their colleagues from the pharmaceutical company Genentech, reported today in the journal Nature the discovery of a variant of the amyloid precursor protein (APP) gene that confers protection against both Alzheimer’s disease (AD) and cognitive decline in the elderly. The findings also indicate a linkage between age-related cognitive decline and late-onset forms of AD, the most common cause of dementia.

“Our results suggest that late-onset Alzheimer‘s disease may represent the extreme of more general age-related decline in cognitive function,” said study lead author Kari Stefansson, M.D., Dr. Med., CEO of deCODE Genetics. “Also important, these data support certain Alzheimer‘s disease drug development programs—some of which are already in human clinical trials.”

Alzhiemer‘s disease is a progressive neurodegenerative disease associated with the production and accumulation of beta-amyloid peptides produced by cleaving bits off the APP. While several mutant forms of the APP gene have been linked to early-onset, aggressive forms of AD, there is limited evidence supporting a role for mutations in the gene in the more common late-onset form of the disease.

In searching for low-frequency variants of the APP gene associated with AD, deCODE scientists found a significant association with a mutation in whole genome sequence data from 1,795 Icelanders. The research team showed that the mutation is significantly more common in the study‘s elderly control group than in those with AD, suggesting that the mutation confers protection against the disease.

The Genentech team then tested these findings using in vitro cellular assays with wild-type APP and APP enriched with A673T, the mutation allele. Importantly, they showed a significanly reduced production of amyloid beta in cells with A673T.

“Our genetic data indicate that the mutation is protective against Alzheimer‘s disease,” said Stefansson. “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.”

Cognitive Decline in the Elderly

To study the assocation of the protective mutation with general cognitive decline, the research team examined the frequency of the mutation in the original Icelandic control group of those cognitively intact at age 85. The team found an enrichment of the mutation in this group, consistent with its protective effect against AD.

Extending this work further, the team investigated cognitive function using a seven-category test in carriers of the mutation and non-carriers in the age range of 80 to 100 years old. The research team found a statistically significant difference between carriers and non-carriers, with the carriers of the mutation having a score indicative of better-conserved cognition. After removing known AD cases, the team again found that carriers had better cognitive function, suggesting that the mutation extends its protective effect to the elderly in general.

"The implication of these data is that general cognitive decline and late-onset Alzheimer‘s disease share biological pathways,” said Stefansson. “It also suggests that approaches to treating Alzheimer’s may have benefit to those elderly who do not carry the protective mutation, and do not suffer from AD.”

Alzheimer’s Disease

Alzheimer’s disease, a progressive neurodegenerative disorder, is the most common form of dementia that affects four to eight percent of the elderly population worldwide. The neuropathological features of AD are the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles in the hippocampus and cortical grey matter of the AD brain.

Age-specific prevalence of AD nearly doubles after age 65, leading to a prevalence of greater than 25 percent in those over the age of 90.

About deCODE

Headquartered in Reykjavik, Iceland, deCODE genetics is a global leader in analyzing and understanding the human genome. Using its unique expertise and population resources, deCODE has discovered genetic risk factors for dozens of common diseases ranging from cardiovascular disease to cancer.

In order to most rapidly realize the value of genetics for human health, deCODE partners with life sciences companies to accelerate their target discovery, validation, and prioritization efforts, yielding improved patient stratification for clinical trials and essential companion diagnostics. deCODE’s corporate information can be found at www.decode.com with information about our genetic testing services at www.decodehealth.com and www.decodeme.com.

http://www.decode.com/news/news.php?story=159

Original content Bob DeMarco, the Alzheimer's Reading Room
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