Alzheimer’s disease is a bit like a murder mystery with numerous possible culprits and only a few vague clues. For years the prime suspect has been a protein fragment called beta-amyloid, which forms clumps inside the brains of dementia patients. Big drug companies since the 1990s have bet heavily on the concept that amyloid poisons brain cells and that blocking it will halt a patient’s devastating decline.
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But even as their drugs move into final human trials, the evidence implicating amyloid is starting to look a little shaky. An amyloid-lowering drug from Myriad Genetics did nothing in a giant trial. Wyeth and Elan’s amyloid-clearing antibody, called bapineuzumab, showed mixed results in a midstage human trial last year. It clearly helped only a subset of patients who lacked a certain gene mutation, and it had side effects such as fluid leakage in the brain.
Stranger yet, this summer researchers from the Mount Sinai School of Medicine in New York City examined an old allergy drug from Russia that recently showed promising results in Alzheimer’s victims. They wanted to know whether it lowered amyloid. To their surprise, it boosted short-term amyloid levels in animal and lab experiments, according to results reported at a big Alzheimer’s conference. Pfizer licensed comarketing rights for the Russian antihistamine from the biotech company Medivation in 2008 for $225 million plus milestone payments, and the companies are conducting large trials. Results are due next year.
All of this has some scientists wondering if they are targeting the wrong chemical. “People inside and outside the amyloid field are trying to think what are we doing wrong. Either we are treating the wrong thing or using the wrong drug or treating it in the wrong way,” says Mount Sinai’s Samuel Gandy, who led the research into the Russian drug and still thinks amyloid is involved. Adds Merck Vice President Richard Hargreaves: “There has been a sort of a narrow-minded approach to Alzheimer’s disease. Amyloid deposition is only one of the features.”
Some go much further. “I think amyloid is a complete nothing,” says University of Aberdeen (Scotland) researcher Claude Wischik. “One day someone has to write a book about how a whole field can get suckered into this for so long.”
Five million Americans suffer from Alzheimer’s disease, and the number will climb as baby boomers age. Existing drugs such as Aricept treat symptoms but don’t stop brain cell death.
While the bulk of research money remains focused on amyloid, some researchers are looking elsewhere. Merck is putting half of its Alzheimer’s research budget into drugs that don’t target amyloid. Harvard Medical School neuroscientist Jie Shen, who thinks amyloid is a mere accomplice, blames the disease on malfunctions in two proteins called presenilin. If her theory is correct, one class of antiamyloid drugs called gamma secretase inhibitors may make the disease worse.
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Some researchers are fingering cousins of amyloid as the killer. Amyloid is produced from a larger protein (amyloid precursor protein) that is chopped up into various fragments, including beta-amyloid. Until now the role of the others hasn’t gotten much attention.
Neuroscientist Marc Tessier-Lavigne, chief scientific officer at Roche’s Genentech division, has intriguing evidence implicating a fragment that binds to something on brain cells called death receptor six, which can trigger cells to die or shrivel and is named for its involvement in a natural self-destruct mechanism. High levels of death receptor six are found in the brain areas that die off in Alzheimer’s disease.
Could death receptor six be the murder weapon in Alzheimer’s? Maybe. Tessier-Lavigne’s evidence is indirect and doesn’t rule out a role for amyloid (which Roche also has drugs against). But unlike amyloid, his fragment provides a clear mechanism for brain-cell death, he says: “This mechanism we have described is very powerful at killing nerve cells.” Under his concept, Alzheimer’s disease results from brain-cell maintenance gone awry. Brain cells constantly prune excess nerve fibers during early development. This landscaping process may go haywire during Alzheimer’s and kill healthy cells, he says. Roche has made antibody drugs that block death receptor six and is testing them in mice with Alzheimer’s symptoms to see if they block memory loss.
Other drug researchers finger two other malfunctioning molecules linked to the disease. One is a protein called tau that makes up the neurofibrillary tangles found in the neurons of Alzheimer’s sufferers. Proponents argue that tangles correlate better with dementia than amyloid plaques do. Merck, TauRx Therapeutics (cofounded by Scotland’s Wischik) and Allon Therapeutics in Vancouver, B.C. are working on drugs that hit tau.
The second is a bad version of a gene called apolipoprotein E. Discovered in 1993, the “bad” form, called APOE e4, can raise the risk of Alzheimer’s disease by a factor of ten for those with two bad copies, and it is involved in 50% to 60% of Alzheimer’s cases. Only 1% of Alzheimer’s sufferers have early-onset forms caused by inherited genes that boost amyloid production. (But two more common genes linked to amyloid were just identified.) “It seems perverse,” says Case Western Reserve researcher Mark Smith, an amyloid theory critic. “We have the major genetic determinant figured out, and few people are working on it.”
One of those few is Robert Mahley, president of the J. David Gladstone Institutes in San Francisco. He has shown that the APOE e4 gene produces a misshapen protein that can glom on to energy producing structures inside neurons called mitochondria and disrupt their function. This may make neurons more prone to damage over time, he says. In 2005 Mahley identified druglike chemicals that can restore the APOE e4 protein to a normal shape. He is collaborating with Merck to devise versions that could one day be tested in patients. One concept would be to treat people with the APOE e4 gene with such drugs in late middle age to prevent dementia from developing, much like cholesterol-lowering drugs are used to prevent heart attacks in those at risk. Still, he laments: “There hasn’t been a lot of attention paid to this. The field has been very myopic.”
Overall, 18 of the 41 drugs in efficacy trials for Alzheimer’s hit amyloid, says market researcher Datamonitor; most of the remaining drugs treat symptoms. The bets keep getting bigger. In July Johnson & Johnson agreed to a $1.5 billion deal to snag an 18.4% stake in Elan and a big share of the profits from bapineuzumab, now in final-stage trials. (The deal may be revised, as it breaches a pact Elan has with Biogen Idec.) Amyloid proponents say early trials were too small to give clear answers. “I think it is pivotal to the disease process,” says Elan Chief Scientific Officer Dale Schenk. “The genetic data in favor of amyloid is enormous.”
The imbalance worries Zaven Khachaturian, former head of Alzheimer’s research at the National Institutes of Health. He fears that if amyloid drugs fail “drug companies will walk away from Alzheimer’s disease as untreatable.” Roche’s Tessier-Lavigne is more optimistic. “It is a perplexing riddle right now,” he says. “In the next several years we will understand how it fits together.”
Alzheimer’s Whodunit
What is killing the brain cells of Alzheimer’s disease sufferers? There are more suspects than in an Agatha Christie murder mystery. Here are a few:
- Beta-amyloid Protein fragments that form plaques inside the brains of Alzheimer’s patients.
- Neurofibrillary tangles Another abnormality found in the brains of victims of Alzheimer’s upon autopsy.
- Apolipoprotein E e4 A common gene variant that markedly boosts Alzheimer’s disease risk.
- N-APP An amyloid cousin that hits a molecule on brain cells called death receptor six.
- Presenilin Two proteins that help neurons function properly and may go bad during Alzheimer’s, says Harvard’s Jie Shen.
- Mitochondria Energy-producing structures in cells that may weaken during Alzheimer’s. Medivation’s drug may protect them.
Source: Forbes.com
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