Mutation Find Bolsters Prospects for Alzheimer’s Drugs

The discovery of a rare genetic mutation that prevents formation of brain plaques associated with Alzheimer’s disease may be proof that the idea behind a new class of drugs in development is valid, scientists said.

Lab tests suggest the variant protects people by preventing an enzyme called beta secretase 1, or BACE-1, from helping create the characteristic beta amyloid tangles in the brains of Alzheimer’s patients, according to the study, published today in the journal Nature. Drugs that mimic this action are in development from Merck & Co., Eli Lilly & Co. and Eisai Co.

The mechanism differs from that of more advanced experimental therapies from Johnson & Johnson, Pfizer Inc. and Lilly that are designed to clear beta amyloid from the brain by binding directly to the protein. The newly discovered mutation, found through genome sequencing, was associated with a 40 percent reduction in beta amyloid in those individuals who had the variant, researchers said.

“Many have been working on attempts to develop treatment with beta-secretase -- they haven’t had any proof of the concept,” said Kari Stefansson, an author of the study and chief executive officer of deCode Genetics Inc., the Reykjavik, Iceland-based company that did the sequencing work. “This natural mutation provides proof.”

Researchers found the mutation by sequencing the genomes of 1,795 Icelanders. The gene also appeared to slow the rate of cognitive decline in 41 people with the mutation who were ages 80 to 100, compared with 3,673 people who didn’t carry the mutation.

Cases Doubling

More than 5 million Americans have Alzheimer’s, which is the most-common type of dementia, according to the Alzheimer’s Association. Global dementia cases are expected to double within the next 20 years to as many as 65.7 million people, the World Health Organization said in April.

Earlier studies found other mutations affecting amyloid precursor protein that were related to a rarer form of Alzheimer’s with early onset. Today’s discovery is linked with the more-common form of late-onset Alzheimer’s, which develops after age 60.

The mutation is only found in about 1 percent of Icelanders, Stefansson said. Still, drug developers could mimic its action of interfering with the beta-secretase that cleaves the amyloid precursor protein to create effective therapies, he said.

Rare Mutation

The significance of the finding isn’t that it can be used clinically; the mutation is too rare for that, said Eric Reiman, chief executive officer of Banner Research, a Phoenix-based medical research institute, and a professor of psychiatry at the University of Arizona. Rather, it’s important because it signals that beta secretase inhibitors, such as Merck’s, expected this year to start the second of three phases of testing usually needed for approval, might be on the right track.

“It provides encouraging evidence that reducing the production of amyloid, and in particular through beta secretase activity matters for preclinical disease,” said Reiman in a telephone interview. “The question is, how early do you need to start?”

The formation of beta amyloid clumps has been associated with Alzheimer’s disease since Alois Alzheimer first described them in 1906. Many researchers theorize that the disease is caused by these plaques.

“If they develop a good effective beta secretase inhibitor, it should be put into the drinking water,” Stefansson said.

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