Scientists fight a narrow view of Alzheimer's cause
SHARON
BEGLEY, The Wall Street Journal
Friday,
April 16, 2004
©2004 Associated Press
(04-16) 06:41 PDT (AP) --
The Journal of Neural Transmission
is no Science or Nature, the two powerhouse research
journals, so even specialists can be forgiven if
they didn't notice a little paper it published last
year. In the study, neurobiologists Glenda Bishop
and Stephen Robinson of Australia's Monash University
found that when they injected the notorious protein
called beta-amyloid into the brains of adult rats,
the results weren't exactly what the dominant theory
of Alzheimer's disease predicts.
As I explained last week, for 20 years
Alzheimer's research has been in the grip of the
amyloid hypothesis. According to this idea, the
disease is caused by the accumulation of sticky
plaques made of beta-amyloid. Yet rat brains injected
with beta-amyloid, Dr. Bishop found, suffered no
more cell death than brains injected with innocuous
salt water.
Amyloid, she concludes, "is not likely
to be directly responsible for the neurodegeneration"
that causes Alzheimer's. Instead, according to evidence
she and others have collected, amyloid is either
an innocent bystander in Alzheimer's or a protector
of a brain under assault from toxic compounds.
That finding is hardly the only challenge
to the amyloid hypothesis. Yet, despite what neurologist
Raymond Kelleher of Harvard Medical School, Boston,
calls "a growing accumulation of evidence that the
amyloid hypothesis is not correct," research that
challenges this dogma fares poorly when it comes
to both funding and publication in the prestige
journals.
With good reason, say some. "The amyloid
hypothesis predominates, it's one of the more mature
areas of research, and most people in the field
think it holds great promise," says William Thies
of the Alzheimer's Association, which nonetheless
funds some nonamyloid research.
As a result, studies supporting alternative
hypotheses have great trouble when they go up against
"the Church of the Holy Amyloid," as neuropathologist
Mark Smith of Case Western Reserve University, Cleveland,
calls it.
When Dr. Bishop submits papers showing
that amyloid might be protective, she says, "I get
strange comments, like 'I just can't believe this,'
but no substantive criticism of what I might have
done wrong. When it comes to Alzheimer's, hardly
anything but amyloid can get a foot in the door."
Editors at Science deny "any particular
editorial bias," and say the papers they publish
"reflect the research underway in the field." But
almost every scientist I spoke to whose work challenges
the amyloid hypothesis has stopped trying to publish
in big-name journals.
The funding situation has been even
worse. "Our grant proposals suggesting an alternative
to the amyloid hypothesis go down in flames," says
Dr. Smith, who has served on panels of the National
Institutes of Health. "Funding agencies told me,
'If it ain't amyloid, it ain't Alzheimer's.' " Since
he and colleague George Perry began their crusade
against the dominance of the amyloid hypothesis,
NIH has not funded any of their Alzheimer's work.
Before that, it did.
At Harvard, molecular neurobiologist
Rachael Neve had three NIH grants a decade ago,
but lost them one by one as her focus switched to
alternatives to the amyloid hypothesis. "They said
I was way out there and refused to renew my grants,"
she says. Even Allen Roses, who in the mid-1990s
discovered that a form of a gene called apoE markedly
increases risk of Alzheimer's, saw his funding evaporate.
"What we were proposing was anathema
to the amyloid people. Our funding (to see what
apoE does in the brain) dried up," says Dr. Roses,
who was then at Duke University, Durham, N.C. "I
had to lay off one-fifth of my lab staff. Although
we got our stuff published, it was in journals that,
if I'd been a young assistant professor, wouldn't
have helped me get tenure." He moved to drug giant
GlaxoSmithKline. But for young researchers in academia,
pursuing alternatives to amyloid is the third rail
of neuroscience.
What makes all this so hard to understand
is that we're not talking about research funding
for, say, divining rods. Challenges to the amyloid
hypothesis rest on solid science.
When you compare one Alzheimer's brain
with another, for example, there is only a weak
correlation between amyloid plaques and loss of
neurons, degree of dementia or synaptic loss. "Amyloid,"
says Dr. Kelleher, "is the poorest correlate of
the pattern and severity of Alzheimer's."
Moreover, since at least 1988, pathologists
who perform brain autopsies have recognized that
amyloid plaques are found in the brains of many
elderly, including those who had no symptoms of
Alzheimer's. In fact, cognitively normal brains
can have more plaques than brains with severe Alzheimer's,
notes Dr. Perry. "Most people over 40 have at least
some amyloid in their brain," he says.
Amyloid, he suspects, "may be trying
to rescue neurons under attack," binding neurotoxic
substances into convenient bundles -- plaques --
so scavenger cells can destroy them. If amyloid
is beneficial or, at worst, neutral, then removing
it won't help a brain beset by Alzheimer's.
Because amyloid research has dominated
Alzheimer's for so long, almost all the experimental
drugs and vaccines in the pipeline are predicated
on the demon amyloid. Now we know why.
©2004 Associated Press
