Biotech Values

[DewDiligence]

Part 2 of Sharon Begley’s WSJ series on Alzheimer’s:

[Thanks to Bob for reminding me of this in the previous post. Please see #msg-2829448 for Part 1 of the series.]

>>
Scientists World-Wide Battle a Narrow View Of Alzheimer's Cause
April 16, 2004; Page A9

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 week1, 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 under way 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.
<<