Whoops

04.04.14

Twenty Years of Alzheimer’s Research May Have Focused on the Wrong Protein

Most researchers think the disease is caused by the build-up of beta amyloid. But over 100 drugs targeting it have failed. Have they been focusing on the wrong protein all this time?

If Claude Wischik is right, almost 20 years of drug development for Alzheimer’s disease have been a costly mistake. Wischik, a chair in mental health at the University of Aberdeen in Aberdeen, Scotland, is a founder of TauRx, a Singapore-based pharmaceutical company. He’s also one of several scientists loudly questioning the focus of most Alzheimer’s research.

Dominating the research field is a protein called beta amyloid, identified by Alois Alzheimer in 1906. Most researchers believe Alzheimer’s disease to be the caused by the accumulation of beta amyloid in the brain. Beta amyloid is sticky and forms plaque, which then strangles healthy cells, according to the amyloid theory of Alzheimer’s disease development. More than 100 drugs targeting beta amyloid have failed. Perhaps the drugs weren’t good, or perhaps the drugs were administered too late to be helpful. Or, if Wischik is right, beta amyloid has been the wrong focus all along.

“It’s extraordinary that in the face of these failed trials, the claims for amyloid remain exactly the same as though there haven’t been any failure,” Wischik said. “There’s been no fundamental revision of the thinking.”

Though tau is promising, it’s hard to get funding for researching it, because many of the scientists making grant decisions are what Wischik calls “members of the Church of the Amyloid.”

Five million Americans age 65 and older currently have Alzheimer’s disease, according to advocacy organization the Alzheimer’s Association. That number is expected to rise to 16 million in 2050. Because dementia results in the gradual loss of capabilities, Alzheimer’s patients require more-expensive care than others on Medicare and Medicaid, totaling $150 billion a year in the U.S.

There is no cure for Alzheimer’s disease, and early diagnostic tests are still controversial. Pharmaceutical company Eli Lilly & Co. developed an imaging agent called Amyvid, which binds to beta amyloid in the brain. It’s a radioactive compound, which means it can be used with MRI machines to determine the amount of beta amyloid in the brain.

To determine if beta amyloid-targeted drugs are failing because they’re administered too late, it will be key to find patients who carry a lot of beta amyloid in the brain but haven’t yet had any symptomatic behaviors. Though the U.S. Food and Drug Administration has approved the $3,000 test, Medicare and Medicaid will only reimburse its use in clinical trials.

Led by Risesa Sperling, researchers at Harvard Medical School will recruit about 1,000 people whose brains show amyloid pathology, and are testing Lilly’s antibody treatment for Alzheimer’s, called solanezumab, for three years. The study is unique because the people recruited won’t have symptoms of dementia when the trial starts. It is the first such trial in late-onset Alzheimer’s disease, and if it fails, it may strike another blow to the amyloid hypothesis. The drug already failed to show any efficacy in two late-stage clinical trials for patients with mild to moderate Alzheimer’s disease. If it fails to protect patients at earlier stages in the disease, it could herald the end of amyloid’s dominance in the field. (It’s worth noting that less than 1 percent of Alzheimer’s patients are early-onset patients. Drugs that help them may not aid late-onset patients.)

Wischik isn’t alone in his amyloid skepticism, either. Mike Williams, editor of the Journal of Biophysiology, says there’s “no evidence” amyloid is causative.

“Amyloid, despite 30 years of research, really hasn’t gotten anywhere,” Williams said. “We’re going to see some major changes if the amyloid hypothesis is totally and utterly wrong.’’

Wischik proposes another mechanism. Beta amyloid, he thinks, is one of many things that can stress cellular garbage disposal in the brain. One of these things is tau, another protein used in cells to hold open channels so they can receive nutrients. When tau misbehaves, it clumps together, and the cells can’t get the food they need. What’s more, once the tau’s gone bad in one area of the brain, there’s a runaway chain reaction in the brain. Slowly, more and more of the tau goes bad, until a patient has Alzheimer’s disease.

In the 1990s, researchers (including Wischik) showed that in human beings, the degeneration of tau tied more directly to the loss of mental capacity than beta amyloid. Though tau is promising, it’s hard to get funding for researching it, because many of the scientists making grant decisions are what Wischik calls “members of the Church of the Amyloid.”

Wischik’s TauRx is putting his money where his mouth is. A compound called TRX-015, targeting sickness-generating type of tau, has enrolled about 900 of more than 1,500 patients in a study. It’s in the last of three phases of clinical study typically required for regulatory approval, and will last fifteen months. Data from the trial will likely appear in the first half of 2016.

Results from a previous study, conducted in 321 people in the UK and Singapore, showed that patients on the study drug, then called Rember, scored 5.5 points better on a 70-point scale cognitive test than those who took placebo. The group who took the study drug didn’t decline in function for more than a year. The most common side effects were diarrhea and discolored urine. Though that study was presented at the scientific meeting of the International Congress on Alzheimer’s and Dementia in 2008, it hasn’t yet been published in a peer-reviewed journal, said Williams. That means that the results should be viewed skeptically, he said.

If TRX-015 doesn’t work, Williams said, there are other approaches to take in the disease, such as limiting inflammation or looking at how mitochondria, the energy storehouses of a cell, go rogue during the course of the disease.

“We’ve still got so many other findings in the wings,” Williams said. “If any of these got prioritized and funded to the extent of amyloid, we might be a lot closer to getting a drug than we are now.”