Science Journal: Alzheimer's research makes dramatic shift

For any normal field of science, the conclusion that "there is more to (fill in a disease) than (fill in leading but unproved hypothesis) alone" wouldn't cause anyone to bat an eye. After all, science is supposed to consider all reasonable ideas. But Alzheimer's disease is not your normal field of science.

Proponents of the leading theory of Alzheimer's have been in pitched battle with scientists who have other ideas about this awful neurodegenerative disease. For more than 20 years, the leading theory has held that sticky blobs in the brain called amyloid plaques cause Alzheimer's. Because that idea has numerous problems, doubters argued that the plaques might be innocent bystanders to the real, "upstream" culprit. If so, targeting the plaques, or the rogue protein called beta-amyloid that forms them, would do nothing to help the 4.5 million Americans who suffer from Alzheimer's.

You might think this debate would play out with each side conducting research, in a "may the best science win" approach. But as I've written before, many scientists whose work challenges the amyloid dogma have been unable to publish in top journals, and their grant proposals, "go down in flames," as Mark Smith of Case Western Reserve University School of Medicine told me. "Among the major journals and funding agencies, the attitude was, 'if it isn't amyloid, it isn't AD.'"

Hence the impact of that "there is more to" statement. It is the focus of a paper in the October issue of the journal Alzheimer's & Dementia reporting on a "research roundtable" convened by the private, nonprofit Alzheimer's Association. Finally, academic scientists and leaders in biotech, medical imaging and big drug companies recognize "there is more to AD than B-amyloid alone," the paper concludes. Which is why the roundtable's goal "was to address, primarily, strategies that do not hinge on directly modulating levels of B-amyloid" (my emphasis).

It's a remarkable turnaround. "This is the first concerted effort by the Alzheimer's Association to focus on things beyond beta-amyloid," says John Trojanowski of the University of Pennsylvania, who has done pioneering work on the role of so-called neurofibrillary tangles in the disease.

To get a sense of what a sea change this is, consider the Alzheimer's drug pipeline. Five drugs have been approved in the U.S. One (tacrine) causes liver toxicity, so is rarely prescribed anymore. None of the other four treat what anyone considers the real cause of the disease. Instead, they nibble around the edges, using strategies to maintain the brain's "cognitive reserve" so that when Alzheimer's sets in you don't become senile quite so fast. None of the drugs provides more than marginal benefit, if that, and help only some patients. And the disease keeps marching through the brain.

Some of the estimated 100 Alzheimer's drugs in clinical trials also nibble around the edges, such as by trying to lower cholesterol or inflammation (thought to worsen Alzheimer's). But of those that aim at a suspected cause of the disease, "the pipeline is full of antiamyloid therapies," says William Theis, vice president for medicine and science at the Alzheimer's Association. "The field was lulled into a false sense of confidence that beta-amyloid was the culprit," says Dr. Trojanowski. "But there is a great deal of uncertainty that the beta-amyloid hypothesis will be validated, although some stalwarts still strongly believe in it. We need to have a balanced portfolio of targets."

Thankfully, there are other suspects for what causes the disease. This month marks the 100th anniversary of Alois Alzheimer's report on his senile patient, Auguste D.: Her brain had stringy tangles inside neurons and "senile plaques" around them. The tangles, it turns out, are made of a protein called tau that gets transformed in such a way that strands of it stick together like cold pasta. The plaques are those globs of beta-amyloid. For many reasons, including the discovery of genes having to do with amyloid, the search for causes and treatment focused on that.

But when you think about it, concluding that B-amyloid and plaques cause Alzheimer's is like believing a scab on your knee causes pain. The scab is the body's response to an earlier injury. Similarly, there is evidence that amyloid plaques don't cause Alzheimer's.

Some elderly people who die with the disease don't have senile plaques. Some who show no sign of dementia do. When an Alzheimer's brain has plaques, they often are not where neurons have died, casting doubt on their toxicity. Also, in people with early Alzheimer's, tau tangles sometimes form before plaques, suggesting that plaques are a response (and maybe a therapeutic one), not a cause. If so, ridding the brain of plaques could cause harm.

"I definitely think it's time to think along other lines of treatment, and that's finally becoming more widespread," says Robert Mahley, president of the nonprofit J. David Gladstone Institutes, San Francisco, and a leading Alzheimer's researcher. "Big pharma has had all its eggs in (the amyloid) basket, and is starting to worry about that."

As a result, there is new emphasis on finding pathologies that lie upstream of beta-amyloid and plaques, or that have nothing to do with them. Next week, I'll discuss some of these ideas and experimental treatments based on them.

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