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Myriad Genetics’ high profile experimental drug Flurizan to treat Alzheimer’s disease recently failed in a pivotal clinical trial, leading some prominent physicians to speculate that research to treat the disease will soon move in a new direction.

The physicians interviewed by Pharmawire discussed a shift in research focus from the current amyloid hypothesis to the tau hypothesis. Two defining features of Alzheimer’s disease in the brain are amyloid plaques and neurofibrillary tangles (tau). The plaques contain a protein called amyloid-beta, while the tangles are made of a protein called tau. The current, widely accepted amyloid hypothesis traces Alzheimer’s to plaque deposits, whereas the tau hypothesis links the disease to protein abnormalities.

Wyeth and Elan are currently developing a drug named bapineuzumab that targets the build-up of amyloid plaques. Indianapolis-based Eli Lilly also has a late-stage gamma secretase inhibitor called LY450139, which aims to reduce plaque build-up by shutting down an enzyme involved in the formation of the amyloid plaques, thereby reducing their concentration in the body. Both drugs are currently in Phase III trials.

Dr G William Rebeck, associate professor in the Department of Neuroscience at Georgetown University Medical Center, said there is no correlation between a patient’s symptoms and the number of plaques they have in the brain, but there is a strong correlation between symptoms and the number of tau tangles.

”You get a lot of tangles around the hippocampus, which is involved in new memory formation. There is a thought that these tangles are closer to the symptoms, and amyloid-beta is further upstream,” he said.

Rebeck believed it is essential for research in the industry to be diverse and explore different targets along the pathway, because it may evolve into combination therapy in the future. Pfizer has just initiated research on its RAGE inhibitors at Georgetown University, which may have the potential to modify the course of Alzheimer’s disease and prevention.

”What we’re going to see is probably a huge shift in the field towards anti-tau based antibodies. It’s currently happening now from investigational drugs to just basic research to see how tau is part of tangle formation,” said Dr P Murali Doraiswamy, chief of biological psychiatry at Duke University Medical. ”We’re at a huge crossroads in the field.”

”There are a lot of resources targeting the amyloid theory and there is not as much effort in targeting tau,” Doraiswamy added.

The old cancer treatment tamoxifen, an orally active selective estrogen receptor modulator (SERM) that is used in the treatment of breast cancer, might have some effect on the tangles. Researchers are also developing antibodies against these tau tangles, and it will only be a matter of time before these antibodies make it into human trials, said Doraiswamy.

”It’s a war that’s been out there for a long time, which moves back and forth between the amyloid and tau theory,” said Dr John L Ratey, associate clinical professor of psychiatry at Harvard Medical School, and recent author of Spark: The Revolutionary New Science of Exercise and the Brain.

”Tau correlates fairly well with cognition. You’re much more likely to produce improvements in cognition, as it is located closer to memory function,” said Doraiswamy.

When there is a failure, the industry moves back to the other side - but it may be the case that both tau and amyloid should be targeted at the same time, some physicians speculated. ”It might be that these two should go hand in hand,” Ratey said.

Dr Marwan Sabbagh, a leading expert in Alzheimer’s research and recent author of The Alzheimer’s Answer, said he can see why development would move into the tau pathway, but the tangles have been harder to tackle. ”Maybe tau is a better marker of disease progression, but it is located in the interneuronal passage,” he added.

”The whole field was working on the amyloid hypothesis, but why aren’t these agents working? To me, is a scary thought that we might have to start over from scratch. The Flurizan data was a real bummer,” said Dr Gregory Jicha, assistant professor of Neurology at the University of Kentucky.

Jicha also mentioned that there are a few companies out there working on other inhibitors like lithium and inhibitors of GSKIII, another enzyme. ”Nobody wants to promote lithium because it’s not patentable. But companies are developing their GSKIII inhibitors,” he said.

Another issue is the industry needs more than one agent in the fight against Alzheimer’s, many physicians argued.

”Any of our clinical trials will be a failure if we have to target both plaques and tangles at the same time. But that would be a nightmare of a trial to design and remarkably complex,” said Jicha.

Dr Ralph A Nixon, associate professor of psychiatry and an amyloid expert at Harvard Medical School and McLean Hospital in Boston, said some of the other parameters, such as tau in cerebral spinal fluid (CSF) would be potentially a more reasonable surrogate marker.

”Most of the efforts have been on amyloid because it has had a lot of support experimentally. Tau is certainly a viable target as well, and there are some things in the pipeline targeting that aspect,” said Nixon.

A lot of new data on investigational compounds in development on the tau pathway will be presented at the upcoming International Conference on Alzheimer’s Disease (ICAD) meeting in Boston later this month. ”It’s not one or the other. There are a number of other modalities or therapies that will operate regardless of the toxic origin of the disease. We have to figure out if it is this specific toxin that’s driving disease progression,” said Nixon.

Researchers and companies should be able to pursue a number of lines of investigation independent of the success and failure of others, added Nixon.

”Unless we are very lucky and come up with a magic bullet that eliminates the need for any other research, which is very unlikely, we need to keep a number of options on the table. My prediction is that people will continue to play out the drugs that are in the pipeline to investigate the role of amyloid,” said Nixon.

”Sooner or later, hopefully we’ll move the field,” said Jicha.

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