JULY 24, 2000 VOL. 156 NO. 3
New Science of Alzheimer's
against timeand one anotherresearchers close in on the aging
brain's most heartbreaking disorder
By J. MADELEINE NASH
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 sadlyas anyone
who has ever watched a parent, a sibling, a spouse succumb to the spreading
darkness knowsthere 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 slowingand perhaps even haltingthe 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 diseaseas
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 explodemore than
threefold by the year 2050, according to some estimates.
ALSO IN TIME
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!"
edition's table of contents
Scientists last week described their progress in finding genes that put
people at risk for Alzheimer's disease. They presented fresh evidence
that other factorshigh-fat diets, for instancemay 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
diseasea sticky snippet of protein known as beta amyloid. A controversial
yet compelling hypothesislong championed by Selkoe, among otherscontends
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
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
It was then that the question of what causes Alzheimer's diseasethe
plaques or the tanglesbegan to loom large. In the mid-1980s, researchers
isolated beta amyloida generic name for a class of sticky proteinsfrom
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
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
casesthose 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 attackedviciously,
he saysand he proceeded to fight back in kind. He dubbed his opposition
the Amyloid People and mercilessly taunted them. The plaques, he arguedand
still argueswere 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 wrongbut 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'sHard to Forgetwriter 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 warsDecoding
Darknessthere 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.
By the mid-1990s, the debate between the Baptists (the first three letters
stand for beta-amyloid protein) and the Tauists had intensifiedand
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 axonslong projections that carry
signals from one nerve cell to anotherholding 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
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 diseasethough
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
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 cox2and not beta amyloidthat
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 reasonsif the faucet is too wide and the drain
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
Cholesterol-lowering drugs, nerve-growth factors, antioxidants, estrogen
replacement in postmenopausal womenthe 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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