TIME EUROPE
July 24, 2000, Vol. 156 No. 4
The New Science of Alzheimer's
Racing against time — and one another — researchers close in on the aging brain's most heartbreaking disorder
By J. MADELEINE NASH
Imagine your brain as a house filled with lights. Now imagine someone turning off the lights one by one. That's what Alzheimer's disease does. It turns off the lights so that the flow of ideas, emotions and memories from one room to the next slows and eventually ceases. And sadly — as anyone who has ever watched a parent, a sibling, a spouse succumb to the spreading darkness knows — there is no way to stop the lights from turning off, no way to switch them back on once they've grown dim. At least not yet.
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>>
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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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