TIME EUROPE
July 24, 2000, Vol. 156 No. 4
The New Science of Alzheimer's
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BAPTISTS VS. TAUISTS
By the mid-1990s, the debate between the Baptists (the first three letters stand for beta-amyloid protein) and the Tauists had intensified — and for a while the Tauists appeared to be gaining ground. For one thing, the normal function of beta amyloid (if it had one) remained mysterious. All that scientists knew was that it was secreted by virtually every cell in the body, that it came primarily in two lengths, and that, in the brain, the slightly longer version was more likely to aggregate into plaques.
Tau, by contrast, clearly played a critical role in the brain. In its normal form it helps support the axons — long projections that carry signals from one nerve cell to another — holding them together like ties on a railroad track. When tau goes bad and clumps into tangles, the axons shrivel up and die. The case for tau further solidified in 1998, when researchers discovered a form of dementia associated with mutations of the tau gene. People with these mutations did not develop the plaques associated with Alzheimer's disease, but at death, their brains were riddled with tangles.
Then, last year, the Amyloid People staged a surprise attack. First, researchers at the South San Francisco laboratories of Dublin's Elan Corp. stunned their colleagues by reporting that they had taken mice genetically engineered to develop plaques and vaccinated them with a fragment of beta amyloid, which apparently spurred the rodents' immune systems to get rid of the dangerous protein. Twelve months later, seven out of nine mice remained plaque free. Then the Elan team vaccinated year-old mice whose brains were riddled with plaques. Result: the plaques started to melt away. Elan quickly drew up plans to test the vaccine in humans. Two dozen Americans have received it and about 40 patients in Britain.
Meanwhile, other research teams, including one led by Selkoe, zeroed in on the elusive enzymes that snip the beta-amyloid fragment from the precursor protein, thus fostering the formation of plaques. "We had the paper, and now we had the scissors," says Selkoe. If he is right, one of those scissors, gamma secretase, may be the presenilin-1 protein. Whatever the true identity of gamma secretase turns out to be, pharmaceutical companies are rushing to develop drugs that block it. Bristol-Myers Squibb has started safety tests of one such compound.
Many questions remain. For example, researchers worry that gamma secretase may perform vital brain functions and that blocking it could cause side effects. Also, no one knows whether strategies aimed at lowering levels of beta amyloid will have any impact on the course of Alzheimer's disease — though if the beta-amyloid hypothesis is right, they should. Selkoe and other Amyloid People see the disease process as a biochemical cascade; the event that triggers the cascade, they believe, is the accumulation of beta amyloid.
In essence, the brain perceives microscopic shards of beta amyloid as foreign bodies, and primitive immune cells called microglia that serve as biological garbage collectors try to clear them away. The result is a state of chronic inflammation that progressively injures nearby nerve cells. Among the weapons the brain's immune system brings to bear are oxygen-free radicals, which is one reason many think that antioxidants like vitamin E may be helpful.
Beyond that, things get murky. It's not yet clear, for example, when tau enters the picture. Up to now, most thought the tangles form much later than the plaques. But neuroscientist Peter Davies of Albert Einstein College of Medicine thinks this view will be proven wrong. He believes some still unidentified biochemical event precedes the formation of tangles and plaques, perhaps a malfunction in the machinery that puts proteins together. He observes: "The question from the therapeutic standpoint is, What's responsible for the symptoms of disease? What's killing the cells? Is it amyloid or tau?"
BEYOND BETA AMYLOID AND TAU
"The question we still need to resolve," muses neurogeneticist John Hardy of the Mayo Clinic in Jacksonville, Florida., "is, What is the relationship between beta amyloid and tau?" That is why Hardy and others are so excited by the new strain of transgenic mice that scientists are breeding. By crossing mice that develop tangles with mice that develop plaques, they should provide scientists with a research tool they've lacked: lab animals that closely approximate the disease in humans.
Over the next several years, researchers can be expected to bring into increasingly sharp focus the enormously complicated molecular pathway of which beta amyloid and tau are just the most visible signposts, and in so doing they are likely to reveal a raft of new opportunities for therapeutic intervention. For example, it appears to be a change in shape that makes tau go bad. Last year Davies and Harvard's Dr. Kun Ping Lu announced that they had found an enzyme that seemed to restore tau to its proper configuration.
Researchers at Mount Sinai School of Medicine in New York City are concentrating on a protein known as COX2, which they have shown rises steeply in the brains of patients in the very early stages of the disease. Cells produce COX2 in response to injury, observes Mount Sinai molecular psychiatrist Giulio Pasinetti, who believes it may be COX2 — and not beta amyloid — that induces the inflammatory response characteristic of the disease. Anti-inflammatories, in other words, could shortly emerge not only as components of the therapeutic arsenal but also as agents of prevention.
One symptom of Alzheimer's is decreased levels of acetylcholine, an important chemical that transmits signals between brain cells. Last week U.S.-based Janssen Pharmaceutica and its Belgian affiliate, Janssen Research Foundation, along with Britain's Shire Pharmaceuticals Group, gained the European Union's approval to market Reminyl (galantamine), a drug that helps boost acetylcholine levels in Alzheimer's patients and improves their memory and language skills.
Selkoe is hoping that APOE4 and other as yet undiscovered susceptibility genes will produce clues that point to other potential compounds. For as he notes, Alzheimer's disease, no less than heart disease and diabetes, will almost certainly be found to have multiple causes. For example, the genes implicated so far in early-onset Alzheimer's all lead to an overproduction of beta amyloid. But the genes involved in the bulk of cases, Selkoe strongly suspects, are more likely to do with faulty clearance mechanisms that aren't doing a good enough job flushing out the plaques. A sink can overflow, he observes, for two reasons — if the faucet is too wide and the drain too narrow.
Scientists are struggling to identify environmental factors that may help protect those who carry susceptibility genes like APOE4. It's clear that these genes in and of themselves are not enough to cause Alzheimer's. Like aging itself, they are risk factors, which means that lifestyle choices may prove equally important. A number of researchers, for example, believe that elevated cholesterol may contribute not only to heart disease but to Alzheimer's as well. Researchers at New York University's Nathan Kline Institute put transgenic mice on high-fat diets, then observed an increase in the rate at which beta amyloid built up in their brains. When they gave the mice a drug that brought cholesterol down, the rate of accumulation slowed.
Cholesterol-lowering drugs, nerve-growth factors, antioxidants, estrogen replacement in postmenopausal women — the verdict on the capacity of such substances to protect against Alzheimer's is not yet in, but it is coming. What is so exciting about the presentations scientists made at the World Alzheimer Congress last week is the staggering breadth of research they reflected. In coming years, Baptists and Tauists alike will undoubtedly encounter setbacks, and the 10 years that the optimists estimate it will take to get on top of this disease could easily stretch into 20 or 30.
For aging baby boomers, that prospect looms as both bitter and sweet. While a sea change in the treatment of Alzheimer's may not occur in time for their parents, it almost certainly will for them.
Reported by Alice Park/New York
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July 24, 2000
COVER
One Is 100
Famous and beloved for her entire adult life, the Queen Mother notches up a century on August 4 — and the celebrations are already in full swing
EUROPE
Crackdown
Moscow's powerful oligarchs feel the heat as Vladimir Putin's tax police and prosecutors continue to make life uncomfortable for Russia's big business
The Hit List
Russia's ruble rousers
Q & A
Berezovsky speaks
The Tax Break Man
By squeezing through sweeping reforms, Chancellor Gerhard Schröder has stolen a march on his critics
BUSINESS
Third Generation Gap
Lower-than-expected bidding for mobile licenses is bad news for governments but good news for consumers
Names in Waiting
The trial is over — now judgment day looms for Lloyd's and investors
HEALTH
The New Science of Alzheimer's
Racing against time — and one another — researchers close in on the aging brain's most heartbreaking disorder
SOCIETY
The French Disease
In France, a best seller exposes a nationwide problem of emotional abuse in the workplace
THE ARTS
In Praise of Flattery
How the rampant sucking up to the famous has undermined the language of private praise
You Look Marvelous!
Tips for kissing up
Irony Is Dead. Long Live Irony (on the Web)
The snide tradition of disrespecting media and movie stars is thriving on delightfully sardonic sites
DEPARTMENTS
Essay
Olympic Monitor
World Watch
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