n the wake of disappointing results this week for yet another experimental Alzheimer’s drug, scientists who have toiled for decades to understand the devastating disease expressed frustration and even anger that their field has not made more progress toward a cure.
“Our field desperately needs new therapies,” Dr. David Knopman, an Alzheimer’s expert at the Mayo Clinic, said at the Alzheimer’s Association International Conference in Toronto, where biotech company TauRx reported the failure of its drug candidate. “In defense, our field is still young,” Knopman added — a justification that dismayed some of his colleagues.
To a growing number of scientists, the problem isn’t that there’s been too little time to make meaningful progress against a hugely complicated disease that strikes an organ unrivaled for its complexity. It’s that the field has made many missteps, that its leaders stifled research that deviated from the dominant theory of what caused Alzheimer’s, and that it was too easy to count as progress journal papers rather than advances that help patients.
“People got into a certain mindset, had a certain set of expectations, and then proceeded on those expectations for 35 years,” said Dr. Daniel Alkon, a 30-year veteran of the National Institutes of Health and now scientific director of the Blanchette Rockefeller Neurosciences Institute in West Virginia. “It was the expectation that amyloid plaques and tau tangles kill brain synapses and neurons,” and that eliminating them will stop the disease, he said. “There were a lot of clues that wasn’t true, but because of their mindset, people didn’t see those clues.”
The idea that Alzheimer’s is caused by sticky clumps of protein called amyloid plaques, which destroy the synapses between brain neurons, dates to the 1980s, and key genetic mutations that cause early-onset forms of it were discovered in the 1980s and 1990s. The discovery that a protein called tau forms “neurofibrillary tangles” that are toxic to neurons dates to 1986, but for decades was overshadowed by the amyloid idea. The animosity between the two camps grew as bitter as a religious war, earning it the name “tauists vs. baptists” (the “ba-” stands for beta-amyloid, the formal name of the protein).
Way back in 1991, however, a study of the autopsied brains of Alzheimer’s patients found that tau tangles and amyloid plaques hardly correlated with the severity of dementia. Loss of synapses did. “But people were blinded by the mindset that amyloid plaques not only must cause Alzheimer’s but be the best target for treating it,” Alkon said, and didn’t entertain the possibility that restoring synapses should be the goal of an Alzheimer’s drug.
In 2008, another team of scientists studied the autopsied brains of Alzheimer’s patients who had been in a study of an experimental Elan drug, an antibody that removed amyloid plaques. They found that a number of the brains had completely cleared amyloid; the antibody worked. But those patients had shown no cognitive improvement.
At minimum, that suggested that by the time amyloid plaques appeared, a brain was too far gone to be rescued with an anti-amyloid drug. But it also raised the possibility that the plaques are markers of cell death, not causes of it, since many people have plaques but not loss of synapses or Alzheimer’s. If so, then destroying amyloid plaques — as many drugs in company pipelines still aim to do and as virtually all the failed drugs did — would not treat the disease. The same might be true of tau tangles, the deadly filaments that form inside neurons and the target of the compound that had disappointing results this week.
The disconnect between plaques and Alzheimer’s “should also have been a wake-up call to everyone that new approaches to Alzheimer’s disease are needed, as almost everyone recognizes now,” Alkon said.
One group that realizes that is the foundation started by Microsoft cofounder Paul Allen. Last year, it awarded $7 million to Alzheimer’s research — on the condition that at least one leader of each of the five teams not be an Alzheimer’s researcher. “We wanted to bring in people and perspectives from outside the field,” Judy Lytle, the former director of the foundation’s program, told STAT at the time.
To be sure, in the last few years both NIH and other funders have opened their wallets to non-amyloid, non-tau approaches to treating Alzheimer’s. Scientists are studying everything from the role of inflammation and microglia, the brain’s immune cells, to that of leakiness in the blood-brain barrier.
“There is no doubt that we have to start looking at things other than amyloid” for drugs to target, Dr. Howard Fillit, executive of the Alzheimer’s Drug Discovery Foundation, which funds many non-amyloid, non-tau research on potential treatments, said recently.
Fillit recalled that when he was a young neurologist in the 1980s, he met with NIH leaders and discussed how “there is immunoglobulin in plaques, there is copper in plaques, there is an inflammatory response,” and more than 400 proteins other than amyloid in plaques. “They basically kicked me out of Bethesda,” uninterested in any Alzheimer’s research other than that on amyloid, he said.
That doesn’t surprise Alkon. “The way the system works at my alma mater [NIH]” is that the outside scientists who advise the agency “tend to fund things they know about and have been working on,” he said. “It’s very conservative, and the system discourages innovation. Advancement in the academic hierarchy depends on conforming, not breaking the rules.”
Another reason for the slow progress toward an Alzheimer’s drug is that “we don’t have great animal models,” said Mayo’s Knopman, vice-chair of the Alzheimer’s Association’s medical and scientific advisory council. “They haven’t been very good at predicting a drug’s effect, and none of them is appropriate for late-onset Alzheimer’s” as opposed to the uncommon early-onset form that results from rare genetic mutations.
Yet scientists kept using the animal models, which yielded publishable studies — the coin of the realm in academia. “The field has known for over 10 years, probably 15 years, that the models were not Alzheimer’s disease and could not predict therapeutic efficacy,” said neurobiologist George Perry, dean of the College of Sciences at the University of Texas at San Antonio. “The models are, at best, models for amyloid and tau deposition, and even that is questionable. These mice never really develop Alzheimer’s.”
It’s not clear where the “other approaches” that Alkon calls for will come from, given the enduring legacy of the amyloid hypothesis on funding decisions. Alkon, working primarily with Rockefeller funding and industry support, focuses on the core pathology of Alzheimer’s — loss of synapses and death of neurons — and has developed a drug called bryostatin. It is being tested in a mid-stage clinical trial sponsored by Neurotrope Bioscience. (Some patients are also receiving it through the “compassionate use” exemption that regulators allow for drugs that have not yet received Food and Drug Administration approval.)
In a paper to be published next week, Alkon and his colleagues describe the molecular steps by which bryostatin increases the production of two key molecules to stimulate the creation of new synapses. “That’s what you need, something that gets at the underlying disease,” said Alkon. “None of the other experimental therapeutics restores lost synapses and prevents neuronal death.”
For now and, it seems, years to come, Alzheimer’s patients will therefore be stuck with the four existing drugs, which have no effect on the disease’s inexorable toll and improve symptoms, such as memory loss, only a little and only temporarily.
“I have to live with [the failure of experimental drugs] every day,” Knopman said, “when I have to tell my patients, ‘This one didn’t work either.’”
Glimmers of hope with non-amyloid, non-tau drugs such as bryostatin suggest that it is not the youth of the Alzheimer’s field that explains why there are no effective treatments.
“I think,” said Fillit, “that with the controversy about the amyloid hypothesis over so many decades, a more balanced approach would have yielded more progress.”