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Alzheimer’s Risk Gene Identified Using Connectome Scan

By BiotechDaily International staff writers
Posted on 20 Mar 2013
Scientists have discovered a new genetic risk factor for Alzheimer’s disease (AD) by screening individual’s DNA and then employing a cutting-edge type of scan to visualize their brains’ connections. The researchers found signs of disease decades before the illness strikes.

The University of California, Los Angeles (UCLA; USA) researchers discovered a common abnormality in the human genetic code that increases the risk of Alzheimer’s. To locate the gene, they used new imaging technology that screens the brain’s connections. Turning off such Alzheimer’s risk genes (in the last 20 years, nine of them have been associated with AD) could block the disorder or delay its onset by many years.

The research is published in the March 4, 2013, online edition of the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS). “We found a change in our genetic code that boosts our risk for Alzheimer’s disease,” said the study’s senior author, Paul Thompson, a UCLA professor of neurology and a member of the UCLA Laboratory of Neuroimaging. “If you have this variant in your DNA, your brain connections are weaker. As you get older, faulty brain connections increase your risk of dementia.”

The researchers, according to Prof. Thompson, screened more than 1,000 people’s DNA to find the common faults in the genetic code that might raise their chance for the disease later in life. The new study was the first of its kind to also give each individual a “connectome scan,” a special type of scan that measures water diffusion in the brain, allowing scientists to map the strength of the brain’s connections.

The new scan, a 4-[F-18]fluoro-N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT1A) molecular imaging probe, was used in conjunction with positron emission tomography (PET) to reveal the brain’s circuitry and how information is directed around the brain, in order to discover risk factors for disease. The researchers then combined these connectivity scans with the extensive genomic screening to pinpoint what causes faulty wiring in the brain.

Hundreds of computers, calculating for months, sieved through more than 4,000 brain connections and the entire genetic code, comparing connection patterns in people with different genetic variations. In individuals whose genetic code differed in one specific gene called SPON1, weaker connections were found between brain centers controlling cognitive functions and emotion. The errant gene also affects how senile plaques gather in the brain—one of the tell-tale marks of AD.

“Much of your risk for disease is written in your DNA, so the genome is a good place to look for new drug targets,” said Prof. Thompson, who in 2009 founded a research network known as Project ENIGMA to pool brain scans and DNA from 26,000 people worldwide. “If we scan your brain and DNA today, we can discover dangerous genes that will undermine your ability to think and plan and will make you ill in the future. If we find these genes now, there is a better chance of new drugs that can switch them off before you or your family [will] get ill.”

Developing new therapeutics for AD is a hot topic for pharmaceutical research, according to Prof. Thompson. The SPON1 gene can also be manipulated to develop new treatments for the debilitating disease, he noted. When the errant gene was modified in mice, it led to cognitive improvements and fewer plaques building up in the brain. AD patients show an accumulation of these senile plaques, which are made of an adhesive substance called amyloid and are thought to kill brain cells, causing irreversible memory loss and personality changes.

Screening genomes has led to many new drug targets in the treatment of cancer, heart disease, arthritis, and brain disorders such as epilepsy. But the UCLA team’s approach—screening genomes and performing brain scans of the same people—have the potential to provide a faster and more efficient search. “With a brain scan that takes half an hour and a DNA scan from a saliva sample, we can search your genes for factors that help or harm your brain’s connections,” Prof. Thompson said. “This opens up a new landscape of discovery in medical science.”

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