Magazine article Clinical Psychiatry News

Amyloid Theory of Alzheimer's Not Dead-Yet

Magazine article Clinical Psychiatry News

Amyloid Theory of Alzheimer's Not Dead-Yet

Article excerpt

The amyloid hypothesis is not dead, but it seems to be limping a bit in the race for an Alzheimer's cure.

Some researchers who predicted 5 years ago that an anti-amyloid disease-modifying therapy was imminent are now re-evaluating that optimism--including the geneticist who first suggested the pathologic link between amyloid plaque deposition and Alzheimer's disease.

"I accept that criticism of myself; it's definitely what I thought," John Hardy, Ph.D., said in an interview. "Everything is taking a lot longer than I thought it would, there's no question about that."

In 1991, Dr. Hardy, a professor of neuroscience at University College London, postulated that [beta]-amyloid deposition was the root of a pathologic cascade that resulted in Alzheimer's disease. The concurrent discovery that a mutation in the amyloid precursor protein (APP) gene caused early-onset Alzheimer's, coupled with the association of plaque deposition and early Alzheimer's in Down syndrome patients, added weight to the theory (Trends Pharmicol. Sci. 1991;12:383-8). A new research boom was born.

The protein was a near-ideal therapeutic target because there are many ways to get at it: immunotherapy to break up existing plaques, compounds to prevent formation of the sticky [beta]-amyloid-42, and antiaggregants to prevent the protein from clumping into neurotoxic plaques. But the first phase III trials of antiamyloid have brought no good news.

Tramiprosate, a [beta]-amyloid antagonist, was the disappointment of 2007; tarenflurbil, a gamma-secretase modulator, this year's downer. And although bapineuzumab, a passive immunotherapy, made it to phase II last summer, positive findings in its phase II trial were slim. A post hoc analysis showed that some patients with mild-moderate Alzheimer's, with no genetic risk factors, had cognitive improvement after getting the vaccine.

Apparently, the finding was enough for Elan Pharmaceuticals Inc., and Wyeth Pharmaceuticals, but maybe not for Dr. Hardy. "The data right now are neither positive nor negative. At this point, the only thing we can say about bapineuzumab is that it's not going to be a miracle therapy," he said.

A long-term follow-up study of patients enrolled in the early AN-1792 immunotherapy trial "doesn't look great for amyloid, either," he said. The AN-1792 trial was halted early, in 2002, when some of the patients developed encephalitis after getting the vaccine. The follow-up, published last summer, showed that the vaccine did clear plaques, but that clearance did not affect cognition or survival (Lancet 2008;372:216-23).

Dr. Hardy doesn't think that slow progress on antiamyloid drugs negates the theory's basic truth, though--at least for a subset of patients. 'A much more open debate is whether the same process is at work in the typical Alzheimer's patient."

But drug companies must target this larger population to create a financially successful therapy, and lack of progress has them fidgeting, he said. "Every drug company is worried now and wondering if they should widen to other therapies, including tau-targeted drugs."

The essential mystery of amyloid further complicates things, Dr. Hardy said: The protein has not yielded up all its secrets, despite years of research. "The thing that keeps me up at night is that we don't really know if amyloid has a function. It could be that amyloid is a response to vascular damage. We all ignore the fact that amyloid deposition occurs to a large extent in the vasculature. …

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