By the end of 1999, scientists plan to begin injecting a small
group of U.S. volunteers with a vaccine against Alzheimer's
disease, the most dreaded age-related malady.
An Alzheimer's vaccine? It's not as far-fetched as it might
sound.
Experts around the world were impressed last summer when
researchers at a San Francisco biotech company published evidence
that a vaccine prevented Alzheimer's-like deposits in the brains of
mice genetically prone to get them.
Not only that, but the vaccine cleared most such plaques from
the brains of mice injected late in life. That raises the
tantalizing possibility of a therapeutic vaccine (as opposed to a
preventive one) for those who have already started showing the
memory loss and other cognitive hallmarks of Alzheimer's.
``It sounds so wacky, but it's a very surprising result which I
completely believe,'' says John Hardy, a leading Alzheimer's
researcher at Mayo Clinic in Jacksonville, Fla.
The vaccine is just one of an expanding array of experimental
drugs targeting Alzheimer's disease in multiple ways. All are aimed
at slowing or even erasing the brain plaques and twisted nerve
fibers called tangles that over time cause a devastating dementia,
robbing patients of their very personhood.
The news is coming thick and fast. Just last Friday, scientists
were buzzing about a report in the journal Science by researchers
at Amgen, a California company, and Brigham and Women's Hospital.
They have discovered an elusive enzyme called beta-secretase,
thought to be critical in the first biochemical step in the
development of Alzheimer's. Other researchers are expected to
report on a different beta-secretase enzyme this week at the
Society for Neuroscience meeting in Miami Beach.
Martin Citron of Amgen says that identifying beta-secretase at
last will accelerate the development of precisely targeted drugs to
inhibit the enzyme, perhaps blocking Alzheimer's at the most
fundamental level.
``The most exciting thing about this finding is that it moves us
up a whole level in terms of having on our hands a drug target,''
says Dr. Rudolph Tanzi, an Alzheimer's researcher at Massachusetts
General Hospital. ``This brings Alzheimer's into the realm of what
AIDS researchers did a few years ago when they came up with HIV
protease as a tangible target. It's a major leap forward.''
Meanwhile, some of the world's leading drug companies already
have far-advanced plans to mount human tests of compounds that
block enzymes called gamma-secretase that are similar to
beta-secretase. And that's just one anti-Alzheimer's approach among
many.
The dawning picture is a startling reversal of the gloom and
fatalism that have surrounded Alzheimer's disease since 1906, when
German neurologist Alois Alzheimer first identified the brain
disorder in a 50-year-old woman known as Augusta D. For the first
time, most researchers now think Alzheimer's will probably yield to
the kinds of combination drug treatments already known to slow or
even reverse the pathology of other diseases, such as
atherosclerosis or HIV infection.
``I think within five to 10 years we'll be treating patients
with drugs that should slow Alzheimer's in people who have it or
prevent it in people who are likely to get it,'' says Dr. Dennis J.
Selkoe of Brigham and Women's Hospital. ``I don't think that's too
optimistic.''
Selkoe is one of the most bullish Alzheimer's researchers. (He
owns stock in Elan Pharmaceuticals, which is developing the
Alzheimer's vaccine and other diagnostic and treatment approaches.)
But Selkoe is hardly the only one who thinks Alzheimer's research
is moving toward practical payoffs.
``I personally feel very optimistic about Alzheimer's
treatment,'' says Hardy, the Mayo Clinic researcher, who is known
for caution.
The first indications of whether new types of anti-Alzheimer's
drugs will work should come within the next 12 to 18 months, from
human trials that are planned or already underway.
Not a moment too soon, either. Alzheimer's already afflicts an
estimated four million Americans _ not to mention their
long-suffering families and the society at large, which must pay
Alzheimer's-related costs totaling up to $100 billion a year. With
rapid aging of the population, there will be four times as many
Alzheimer's patients as there are today when the last of the baby
boomers approach retirement age in 2028.
New treatment approaches were impossible before scientists began
to understand the silent sequence of events that lead to
Alzheimer's, a 15-year quest that has had more than its share of
frustrations.
The first clues came from individuals with Down's syndrome, who
are born with an extra chromosome 21 (out of the 23 chromosome
pairs in humans). People with Down's invariably develop Alzheimer's
disease if they live long enough. Autopsies of Down's children who
died of other causes found extensive plaques and tangles in their
brains as early as age 12, which may imply that the damage began
before birth.
A dozen years ago, scientists discovered the reason. The gene
for a protein called APP (for amyloid precursor protein) resides on
chromosome 21, the very one that Down's individuals have an extra
``dose'' of. Although researchers aren't sure why, APP is normally
made by many cells in the body; but when APP is enzymatically
snipped in a certain way, it becomes a protein called amyloid-beta,
or A-beta. And A-beta is the main ingredient of Alzheimer's
plaques.
That observation set researchers on the amyloid trail, trying to
puzzle out whether excess A-beta is a cause of Alzheimer's or
merely the trash that builds up as a result of brain damage from
another cause. The next clue came from genetic studies of families
cursed by Alzheimer's in successive generations.
In 1991, Hardy and his colleagues discovered the first such
familial Alzheimer's mutation. Significantly, it was in the APP
gene, right in the region that codes for the A-beta fragment.
Since then, researchers have found four different Alzheimer's
genes, which together may account for a quarter of all cases; more
undoubtedly lurk undiscovered. ``I expect one to two dozen common
DNA variations determine the overall risk of Alzheimer's,'' says
the MGH's Tanzi, who is currently combing the entire gene sets of
400 families for the undiscovered Alzheimer's risk factors.
The multigene character of Alzheimer's could be bad news. It
might imply that the disease labelled Alzheimer's is a collection
of different diseases, presumably requiring many different
treatment or prevention approaches _ and a concomitant nightmare of
determining just who should get what treatment.
Instead, most (but not all) researchers now believe in a unitary
notion of Alzheimer's. Perhaps more important in terms of research
investment, so do leading drug companies.
They're betting on what is called the ``amyloid hypothesis,''
which holds that the basic flaw lies in the overproduction of
A-beta (specifically, a particularly pernicious type called A-beta
42, which clumps into insoluble filaments).
Selkoe thinks atherosclerosis may be an apt analogy. In that
disease, many genes also contribute to the deposition of fatty
plaques within artery walls, in combination with environmental
factors. The body's response to this arterial sludge _ perhaps a
defense mechanism gone awry _ converts the underlying disease
process into the catastrophe of a heart attack or stroke. Drugs
aimed at multiple points in this complex process have lately been
able to reverse this accumulating risk to a great extent.
As with Alzheimer's, there are risk factors and genetic markers
for atherosclerosis, but the known risk factors don't explain a
sizable proportion of the cases. In Alzheimer's, for instance,
people with one or two copies of a gene called ApoE-4 have four to
10 times the risk of dementia.
It may be that people with ApoE-4 are less efficient in clearing
A-beta 42 from their systems than those with other forms of ApoE.
But ApoE-4 by itself is not sufficient to cause the accumulation of
A-beta leading to Alzheimer's; curiously, some with two ApoE-4
genes remain mentally sharp into their 90s. For that reason, ApoE-4
is not a very useful marker for Alzheimer's risk, and neither is
the presence of A-beta in the blood or spinal fluid.
At the moment, many researchers are betting that the best hope
for treating and preventing Alzheimer's is to prevent or slow the
production of A-beta 42 _ either with a vaccine or by blocking the
enzymes that clip its precursor protein, APP, in the ``wrong''
place.
Will it be safe to give people drugs that inhibit these enzymes?
After all, some are known to be involved in the processing of an
important protein dubbed Notch, a cell-surface receptor that guides
the maturation of various immune cells. And last week Yale
University scientist Pasko Rakic and his colleagues reported in
Science that the Notch receptor regulates nerve cell growth in
adult brains _ a finding that may turn out to be useful in
understanding many diseases, but may also be a warning flag that
Notch should not be fooled with lightly.
Selkoe, in reply, notes that some scientists have found it takes
very little Notch protein to carry out its necessary functions, so
it may be safe to turn down its production a little. ``If I lowered
Notch production by 40 percent, it might not interfere with its
necessary function, but if I lowered a-beta production by 40
percent, it might be enough to slow the formation of Alzheimer's
plaques,'' he hypothesizes.
In any case, attacking A-beta with enzyme inhibitors and
vaccines does not represent the only arrow in Alzheimer's
researchers' quiver.
Because nerve cell damage may be partly due to inflammation
kicked up by Alzheimer's plaques and tangles, companies are testing
anti-inflammatory drugs to see if they can slow the disease.
Oxidation damage may also play a role, so researchers are testing
anti-oxidants such as vitamin E and gingko biloba.
Others are testing a slew of compounds that protect nerve cells
or may even regenerate them, including the female hormone estrogen
or its newer, more selective synthetic forms.
Also in the pipeline are new variants of the only current drug
used to treat Alzheimer's, called Aricept. These drugs boost a
brain chemical called acetylcholine that allows some nerve cells to
communicate with others, which is depleted in Alzheimer's patients.
So far it appears such drugs only modestly delay the progression of
Alzheimer's, but a report last week by Ole Isacson of McLean
Hospital in Belmont may increase interest in them. Isacson reported
that boosting acetylcholine in rats' brains decreased APP, the
A-beta precursor.
Whatever turns out to work, it's important to keep in mind that
no Alzheimer's treatment (alone or in combination) needs to cure
the disease. It may well be enough to slow it down and keep it
within manageable bounds.
``If we could change the average date of symptom onset by a
decade, we could essentially `eliminate' Alzheimer's disease in
about 13 million people, who would die of something else before
they got Alzheimer's,'' notes Dr. Trey Sunderland of the National
Institute of Mental Health in Bethesda, Md. ``That's really where
we are headed.''
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