Copper, Zinc, and Alzheimer’s

March 25th, 2010

(2003) I received this today from a friend who’s interested in alternative medicine. I pass it along for comment. I’ve shortened the original article, which was quite lengthy.

Maverick Scientist Is Winning Converts On Alzheimer’s

Dr. Bush Was Widely Derided When He Said Zinc, Copper Played Role in Disease


BOSTON — Ashley Bush, a 44-year-old researcher at Harvard Medical School, was pilloried after he put forth a radical theory of Alzheimer’s disease in 1994.

"Worthless," wrote one scientific critic. Others have described his style as brash, his content as flimsy, and his ideas unworthy of being published. At worst, Dr. Bush recalled, it felt like "hate mail."

Over the years, he submitted 30 scientific papers that were rejected by scientific journals. Eight times, his grant applications were spurned by the National Institutes of Health.

Dr. Bush’s theory is that the real culprit in Alzheimer’s is a copper and zinc buildup in the brain — an idea few scientists have looked at. He believes the accumulated metals mix abnormally with a protein called beta amyloid in the brain, oxidizing — literally rusting — and destroying nerve cells. Published in the prestigious journal Science, his hypothesis swiftly drew criticism because it ran counter to the leading theory that Alzheimer’s disease is caused mainly by the protein clumps themselves. And by highlighting metals as the culprit, it drew scowls from some who thought it resembled a largely discredited theory that aluminum caused the disease. (He never saw aluminum as a culprit.)

Now scientists are giving Dr. Bush more credence. He has a five-year grant from the NIH and this year won an American Academy of Neurology prize for Alzheimer’s disease research.

One big reason: He is on the trail of a drug that absorbs his culprits — the excess copper and zinc — and dissolves the protein clumps in the brains of experimental animals. Dr. Bush has found a potential Alzheimer’s treatment in a 70-year-old dysentery drug with a history of toxic side effects. What’s more, he and his colleagues this month published their first human clinical trial showing the drug’s promise. "It’s like Drano," he says. "It blows them away."

The small trial’s results are "significant" and "innovative," says Roger Rosenberg, a neurologist at the University of Texas Southwestern Medical Center and editor of the Archives of Neurology, which published the research.

Dr. Bush’s odyssey shows how rejects in the world of science can sometimes re-emerge as important figures. The history of science in the last 50 years could be written with papers rejected by prestigious journals, observed Paul Lauterbur of the University of Illinois after he won the 2003 Nobel Prize for medicine…

In Dr. Bush’s view, amyloid protein plays a helpful role in the brain: absorbing metals like a sponge. But in Alzheimer’s victims, he contends, the metals overwhelm the protein. He believes that copper mixes abnormally with amyloid, releasing hydrogen peroxide and other toxic chemicals that damage the nearby cells. Some of that protein breaks free, becomes "rogue" amyloid, and mixes with zinc to form clumps that leak more hydrogen peroxide. Thus he indicts metals as the real culprits. This theory is still controversial.

Some critics see his metals theory as mere speculation. "Based on science, there is no substantiation for what Ashley says," says Bruce Yankner, professor of neurology at Harvard. "Ashley’s ideas are interesting. But that’s what they are — interesting."

One problem in verifying Dr. Bush’s hypothesis is the difficulty of measuring copper or zinc in the human brain. Many scientists believe trace amounts of metals exist in the brain, but Dr. Bush contends that excessive amounts build up in some aged people. Among unanswered questions is where the metal buildup comes from. Dr. Bush doesn’t claim to know…

Meanwhile at closed-door NIH meetings, grant reviewers weren’t so jocular. They issued a pointed challenge to his work, Dr. Bush recalls. He says these outside experts asked: "If you are so sure this is the cause of Alzheimer’s disease, where is your drug?"

"Why am I having such a difficult time?" Dr. Bush recalls asking NIH after his rejections.

But it turned out that Dr. Bush had an ally at NIH. He was Stephen Snyder, a Ph.D. in pathology at the National Institute on Aging. Dr. Snyder oversees grant applications dealing with the origins of Alzheimer’s. He heard reviewers complain because Dr. Bush’s applications were long on brain chemistry and short on biology. Dr. Snyder passed all this along to Dr. Bush, and vowed to help Dr. Bush improve his applications.

It also turned out that Dr. Bush was indeed pursuing a treatment. Working with mice given a gene for Alzheimer’s, Dr. Bush tested oral doses of a 70-year-old drug called clioquinol, versus placebos. When Dr. Snyder learned of this, he quickly asked to see the data. After nine weeks, the treated mice had a 49% reduction of beta amyloid deposits.

"Holy Finoki!" Dr. Bush e-mailed Dr. Tanzi.

In late 1999, Dr. Bush sent a photographic slide of the results to the aging institute. Dr. Snyder remembers thinking, "Wow. This doesn’t come along every day.’ The placebo mice had huge plaques. The treated mice had brains as clear as the day they were born." He recalls deciding, "I’m going to go to the wall for this."

Dr. Bush crafted his ninth NIH grant proposal. The review committee gave it a score in the top third — not great, but enough to get a $750,000, five-year grant.

"The mice came along at the right time," Dr. Snyder says. The journal Neuron published the mouse study. In Melbourne, Prana, the biotech company Dr. Bush co-founded, prepared to launch human clinical trials.

But there was a problem: Clioquinol had a disastrous history. It was introduced in the 1930s by Swiss drug giant Ciba-Geigy AG, as a treatment for amoebic dysentery, a potentially deadly intestinal ailment. The drug was later promoted in Japan for all types of stomach trouble. By 1970, however, nearly 10,000 people who had been treated with the drug, mostly in Japan, developed paralysis or blindness.

These days, some scientists believe the adverse effects might have been influenced by a vitamin B-12 deficiency in the postwar Japanese diet. So Prana added vitamin B-12 supplements to the clioquinol in the Alzheimer’s study. That did the trick, the company says.

Prana’s randomized double-blind clinical trial was launched in 2000 and completed by 32 volunteers in 2002. Half of them got clioquinol; half got a placebo. In spring of 2002, Colin Masters, chairman of Prana’s scientific board, gave the first peek at the results, declaring Alzheimer’s disease was slowed by the drug.

This month the Archives of Neurology published the full report. The results: Volunteers on placebo showed a "substantial worsening" of the disease based upon cognitive tests, while people on clioquinol experienced "minimal deterioration." In addition, blood levels of beta amyloid protein in the blood declined among those taking the drug but increased in those on placebo. As for side effects, the drug was "well-tolerated," wrote Dr. Bush and his co-authors from the U.S., Europe and Australia. One participant, who had a history of hypertension and glaucoma, suffered impaired vision during the trial. But the symptoms disappeared when the trial ended…

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