But sooner than one might have dared hope, predicts Harvard University neurologist Dr. Dennis Selkoe, Alzheimer's disease will shed the veneer of invincibility that makes it such a terrifying affliction. Medical practitioners, he believes, will shortly have on hand not one but several drugs capable of slowing — and perhaps even halting — the disease's progress. Best of all, a better understanding of the genetic and environmental risk factors will lead to earlier diagnosis, so that patients will receive treatment before their brains start to fade.
Could Selkoe be right? Could it be that patients and physicians will view Alzheimer's disease in the same way they now view heart disease — as a serious illness that can be treated and even prevented? That's what Alzheimer's experts are hoping. Already, they observe, an estimated 12 million people are suffering from the disease worldwide. And as the population grows and people live longer, those numbers will explode — more than threefold by the year 2050, according to some estimates.
Last week, as Alzheimer's researchers gathered from around the globe for the giant World Alzheimer Congress 2000 in Washington, there was a dawning sense that scientists could be on the verge of stemming the epidemic. In recent years, new and startling insights into Alzheimer's have started to pour out of university, government and corporate laboratories. And thanks to an influx of interest and research dollars, the pace of discovery is accelerating. Exclaims Marcelle Morrison-Bogorad, who heads the Neuroscience and Neuropsychology of Aging Program at the National Institutes of Health in the U.S.: "An awful lot of scientists are following an awful lot of leads, and the leads are tantalizing!"
Scientists last week described their progress in finding genes that put people at risk for Alzheimer's disease. They presented fresh evidence that other factors — high-fat diets, for instance — may elevate that risk. And most exciting of all, they discussed the first clinical trials of compounds that target what many believe to be the cause of Alzheimer's disease — a sticky snippet of protein known as beta amyloid. A controversial yet compelling hypothesis — long championed by Selkoe, among others — contends that excessive amounts of beta amyloid are toxic to neurons in the same way that too much cholesterol hurts the cells in blood-vessel walls.
Indeed, unless these clinical trials run into unexpected snafus, a long and fierce debate may soon be resolved. Observes Bill Thies, vice president of medical and scientific affairs at the Alzheimer's Association in Chicago: "Either the beta-amyloid hypothesis is correct, in which case new therapies should come very quickly, or it isn't, in which case researchers at major laboratories will very quickly switch their efforts to more productive directions."
JOUSTING FOR GENES
For nearly a century, scientists have wondered which of the brain lesions associated with Alzheimer's is more important. Is it the plaques, filled with beta amyloid, that litter the empty spaces between nerve cells, or the stringy tangles, composed of another protein called tau, that erupt from within? The problem arose the moment a German neuropathologist named Alois Alzheimer stared through a microscope at a slice of brain tissue and beheld these twin markers of the disease he was first to diagnose. The year was 1906. The patient's name was Auguste D. She was 55 when she died, and she had spent the last years of her life as a patient in a mental institution. She was prone, Alzheimer noted, to angry outbursts and fits of paranoia, and would sometimes pat the faces of others, apparently mistaking them for her own.
Alzheimer's discovery generated great interest at the time, but the disease that carried his name soon came to be regarded as a medical oddity. Why? For many years, the diagnosis appeared to apply only to a very small group of patients under the age of 60. That soon changed, thanks in part to the widespread use of vaccines and antibiotics, which extended the life span. By the 1960s, the number of cases of so-called senile dementia had increased to the point that neurologists finally made the connection: in most cases, Alzheimer's disease and senile dementia were one and the same.
It was then that the question of what causes Alzheimer's disease — the plaques or the tangles — began to loom large. In the mid-1980s, researchers isolated beta amyloid — a generic name for a class of sticky proteins — from the brains of Alzheimer's patients. A short time later, four research teams zeroed in on the gene that encodes the recipe for making the protein. To their great surprise, they discovered that beta amyloid was a fragment of a much larger protein, which came to be known as the amyloid-precursor protein, or app for short.
Almost overnight, it seemed, scientific interest in the genetics of beta amyloid exploded. Researchers had long been aware that early-onset Alzheimer's, while rare, often ran in families. Could it be, they wondered, that the culprit was a mutant version of the app gene? In 1991 scientists at London's St. Mary's Hospital Medical School screened the dna of an Alzheimer's family and found what every geneticist in the field had been furiously looking for. The mutant app gene sat on chromosome 21, and the single change in its dna sequence occurred in the vicinity of the beta-amyloid fragment.
Sometime later, two more early-onset Alzheimer's genes were found, presenilin-1 and presenilin-2. Like APP, these genes were dominant; a child who received just one gene from either parent would inevitably get the disease. One of the most tragic examples involved a 4,000-member Colombian family that had been haunted for generations by Alzheimer's. Yet such cases, researchers were well aware, accounted for a small fraction of cases of Alzheimer's. Still other genes, they reasoned, must be involved in the majority of cases — those in which dementia does not strike until age 60 or later.
In 1992 Dr. Allen Roses, a rapier-tongued contrarian then at Duke University, challenged the beta-amyloid orthodoxy. He announced that he and his colleagues had found a major Alzheimer's-susceptibility gene that affected the late-onset forms of the disease. It was the gene for APOE4, a common variant of the APOE lipoprotein, which is one of the many workhorses of the body's cholesterol-transport system. What, everyone wondered, could this lipoprotein, a known risk factor for heart disease, possibly have to do with Alzheimer's? Many thought Roses could not be right.
What followed was a sustained scientific Donnybrook. Roses, whose penchant for plain speaking had long irritated his peers, was attacked — viciously, he says — and he proceeded to fight back in kind. He dubbed his opposition the Amyloid People and mercilessly taunted them. The plaques, he argued — and still argues — were just tombstones, markers of places where brain cells had died, not the cause of death. On one occasion, Roses sent Selkoe, who had co-founded a company to work on Alzheimer's therapeutics, a photograph inscribed with the message "Dennis, you're wrong — but you're going to be rich."
In the end, Roses won the APOE4 argument. Everyone now agrees that this gene is indeed a major risk factor for Alzheimer's disease. But unlike app and presenilins, it is a susceptibility gene. People who carry it do not invariably develop Alzheimer's, but if they do, their brains appear to be more riddled with plaques and tangles than the brains of Alzheimer's patients who carry slightly different versions of the APOE gene. Even more intriguing, APOE4 appears to have a broad impact on the well-being of nerve cells. People who carry two copies of APOE4 have more difficulty recovering from strokes and traumatic head injuries; they are also more likely to sustain brain damage during cardiovascular surgery.
In all, APOE4 may contribute to the development of more than 60% of all late-onset Alzheimer's cases. But that leaves the other 40% unaccounted for. Many scientists, including Roses, are now racing to identify still other Alzheimer's-susceptibility genes. Rudolph Tanzi, a geneticist from Harvard, believes that he has nabbed a prime suspect on chromosome 12, a gene called A2M. But he has yet to convince his critics. Two years ago, when Tanzi presented his data at an Alzheimer's meeting in Amsterdam, his evidence was brutally attacked. "I wish I'd been wearing chain mail," he jokes. "I felt as if I'd been shot through with spears and arrows."
The dispute over A2M still smolders. Roses, now director of genetics at Glaxo Wellcome, says he looked at that gene. "I even filed a patent on it," he says with a grin. But he's convinced it's not the right gene. Tanzi, however, won't admit defeat. "There's a ton of biology that suggests it's a good candidate," he says. A2M may affect the rate at which neurons produce beta amyloid.
In his poignant, eloquent memoir about his late father's struggle with Alzheimer's — Hard to Forget — writer Charles Pierce describes his dismay at the often savage sparring that he witnessed firsthand among scientists. It made him "want to throw things," he writes, "to scream at all these brilliant people that I didn't care a damn about which one of them got to be first as long as someone was." And yet, as Tanzi observes in his soon to be published account of the Alzheimer's wars — Decoding Darkness — there is another way to look at the extreme contentiousness that has for so long characterized the field. He believes "that the hot sparks of conflict, singeing so many of our butts, were making us charge forward as fast as we could go."
If the competition in the Alzheimer's field seems exceptionally intense, it's because the stakes are so high. Any drug that can stem or stop or prevent this disease, it is estimated, would easily generate revenue of several billion dollars a year. MORE>>
Page One | Two
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