Oct. 14, 2002 -- When it made mice with Alzheimer's
disease regain mental function, it looked like a cure. When it made
people's brains swell dangerously, it looked like a disaster.
Between these two extremes, a promising vaccine now points the way
to new Alzheimer's treatments.
The idea behind the vaccine -- Elan Corp.'s AN1792
-- is simple. It harnesses the power of the immune system to attack
the plaques that clog the Alzheimer's patients' brains.
To do this, the vaccine uses a synthetic version of
the plaque's main ingredient, beta amyloid (Aß). This 42-piece
synthetic molecule, dubbed Aß42, causes the immune system
to make Aß-blocking antibodies. Special mice bred to develop
Alzheimer's disease do a lot better when vaccinated with Aß42.
Unfortunately, human trials found that about 6% of
Alzheimer's patients injected with Aß42 developed a
dangerous brain swelling. The cause of this inflammation wasn't
clear. Now further study of these patients shows that vaccinated
patients developed powerful anti-Aß antibodies. Whatever it was that
caused the brain inflammation, these antibodies don't seem to be the
culprit. The antibodies avidly attacked plaque -- but not human
brain cells.
That's very good news, says study leader Roger M.
Nitsch, MD, director of psychiatry research at the University of
Zurich, Switzerland. Nitsch and colleagues report their findings in
the Oct. 15 online issue of Nature Medicine.
"The high degree of specificity of the antibodies is
a remarkable finding. It argues in favor of the vaccination
strategy," Nitsch tells WebMD. "We were pleased by the absence of
unwanted cross-reactions with normal brain cells."
Of course, it's one thing to attack plaque, and
another thing to stop the awful march of Alzheimer's disease. Nitsch
and colleagues are carefully watching people who got the vaccine in
European and U.S. studies. By next summer they should know whether
the patients are doing better.
"Clearly, further research is required to improve
the safety of this novel therapeutic strategy," Nitsch says. "Our
patients are now carefully followed up to determine whether the
vaccination is effective in preventing cognitive decline and
progression of dementia."
Big help comes from another research group led by
JoAnne McLaurin, PhD, at Canada's University of Toronto. This team
was the first to show that the Elan vaccine could improve
Alzheimer's symptoms in mice. Now they have the found the key to why
the vaccine works, why it causes brain inflammation, and -- most
important -- how it might be improved.
In the same issue of Nature Medicine, the
McLaurin team reports that a small piece of Aß42 -- Aß4-10
-- raises the same plaque-stopping antibodies as the larger
molecule. And in mouse studies, it doesn't cause brain inflammation.
Some part of the larger molecule apparently triggers immune
responses linked to inflammation.
McLaurin says it looks like the small segment of
amyloid protein attacked by anti-Aß4-10 antibodies may be
the main troublemaker in Alzheimer's disease. This target appears to
be essential for amyloid to self-assemble into plaque.
"The theory -- and I stress that this is only a
theory -- is that the anti-Aß4-10 antibody targets an
amyloid assembly product, and by pricking out this one product you
stop neuronal loss," McLaurin tells WebMD.
It may be that using Aß4-10 as a vaccine
would be safer and as effective as the previous version of the Elan
vaccine. On the other hand, Nitsch says, it might be better to treat
patients with antibody itself -- a strategy known as passive
immunization. Or it might be possible to give the vaccine along with
drugs to prevent brain inflammation.
McLaurin's team is working on another approach.
They're looking for a small molecule that mimics anti-Aß4-10
antibodies. The hope is that such a drug would be small enough to
penetrate the brain and stop Alzheimer's disease cold in its tracks.
And since people vary enormously in their response to vaccines, an
anti-Aß4-10-like drug likely would work for more
patients.
What kind of hope does this offer for people who
have Alzheimer's disease today? McLaurin warns that research is
still in its early stages, but she holds out hope that this approach
might work.
"Someone who has florid Alzheimer's disease right
now is probably too far along," she says. "But someone in the early
stages of the disease has potential to be in clinical trials that
will come along. Potentially it will halt the disease -- but it
won't bring back anything that they have lost."
