The Tangled Neuron: Controversy over the Causes of Alzheimer's
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Controversy over the Causes of Alzheimer's
Summary: Dr. Rudy Castellani of the University of Maryland has received the 2010 Journal of Alzheimer’s Disease outstanding contribution award for his article criticizing the popular hypothesis that a protein called beta amyloid causes Alzheimer’s. The award highlights the growing disagreement about the causes of Alzheimer’s.
Alzheimer’s is caused by plaques and tangles in the brain, right? Wrong, says a group of researchers who believe that focusing on these abnormal proteins is keeping scientists from investigating other potential causes.
In a 2009 article in the Journal of Alzheimer’s Disease, they wrote that the popular hypothesis that beta amyloid (the protein found in plaques) causes dementia is flawed. This flawed hypothesis is why potential Alzheimer’s drugs continue to fail in clinical trials, they said, and has caused unnecessary suffering for patients and families.
Last month, the 300+ Associate Editors of the Journal of Alzheimer’s Disease voted to give Dr. Rudy Castellani, the lead author of this article, the Journal’s annual award for outstanding contribution. The award highlights the growing disagreement about the causes of Alzheimer’s.
Dr. Castellani is Professor of Pathology and Director of Neuropathology at the University of Maryland. The two Editors-in-Chief of the journal, Mark Smith and George Perry, are co-authors of the paper, and with Dr. Castellani, have long hypothesizedthat events earlier in the disease process, not beta amyloid, cause Alzheimer’s. Their logic goes something like this:
Alzheimer’s is caused by plaques and tangles in the brain, right? Wrong, says a group of researchers who believe that focusing on these abnormal proteins is keeping scientists from investigating other potential causes.
In a 2009 article in the Journal of Alzheimer’s Disease, they wrote that the popular hypothesis that beta amyloid (the protein found in plaques) causes dementia is flawed. This flawed hypothesis is why potential Alzheimer’s drugs continue to fail in clinical trials, they said, and has caused unnecessary suffering for patients and families.
Last month, the 300+ Associate Editors of the Journal of Alzheimer’s Disease voted to give Dr. Rudy Castellani, the lead author of this article, the Journal’s annual award for outstanding contribution. The award highlights the growing disagreement about the causes of Alzheimer’s.
Dr. Castellani is Professor of Pathology and Director of Neuropathology at the University of Maryland. The two Editors-in-Chief of the journal, Mark Smith and George Perry, are co-authors of the paper, and with Dr. Castellani, have long hypothesizedthat events earlier in the disease process, not beta amyloid, cause Alzheimer’s. Their logic goes something like this:
- Abnormal accumulations of beta amyloid (the protein in plaques) and tau (the protein in tangles) are not harmful, and are simply end-stage signs of earlier problems
- Recent research indicates that beta amyloid may be protective – a normal immune response and an anti-oxidant
- The accumulation of beta amyloid that can be seen at autopsy (and on new brains scans) is not well correlated with dementia
- The focus on these abnormal proteins has crowded out funding needed to research other hypotheses.
Still the Main Hypothesis, At Least in Public
Dr. Castellani and his co-authors are not alone in their thinking. In the five years I’ve been blogging, many researchers have privately told me they think the amyloid hypothesis is wrong and that Alzheimer’s research is headed in the wrong direction. In the last couple of years, this discussion has become more open at research and public events (a webcast event at the University of Pennsylvania and ICAD 2008, for example). So why is the amyloid hypothesis still the main theory in Alzheimer’s research?
“Based on my interaction with various neuroscientists and clinicians in the field, the dominant hypothesis -- the so-called amyloid cascade, now the synaptic abeta hypothesis -- is widely viewed as seriously flawed,” says Dr. Castellani. “Unfortunately, there is a lot of money and associated influence, as well as prestigious names and titles with a personal stake in the ultimate success of treatment efforts modeled after their preferred construct. Alzheimer’s research involves selling ideas as much as (and more in my view) objective pursuit of knowledge. In this respect, the peer review process is a bit of a farce, as it encourages fealty to existing ideas and hampers innovation, in spite of unending lip service paid to the latter.”
And if there are doubts about the amyloid hypothesis, why do presentations and articles about Alzheimer’s for a lay audience often present it as fact? “The popular press (major media outlets, many of them) will run articles, with or without schematic representations, along with quotes from esteemed researchers at the world’s top institutions,” says Dr. Castellani. “They speak of (overly simplistic) removal of bad proteins, the exciting results from (hopelessly irrelevant) experimental models, economic burdens to society if something isn’t done, anecdotal accounts of human intervention, etc, etc. All this, which taken together amounts to no more than snake oil in terms of a cure, permeates public thought and pretty soon everyone wants to be vaccinated [against beta amyloid]. Lost in the process is a hypothesis that is deeply flawed and certainly unproven.”
A Lot at Stake
The amyloid hypothesis, right or wrong, is important because a large number of potential Alzheimer’s treatments are based on it. If it’s wrong, the hopes of patients and families will continue to be dashed, and millions of dollars will have been wasted on drug development. [It seems ironic that the cash prize associated with the award Dr. Castellani received is sponsored by Elan Pharmaceuticals, which is developing potential Alzheimer’s treatments based on the amyloid hypothesis.]
If it’s wrong, people enrolled in clinical trials of amyloid-lowering treatments are being subjected to unnecessary risk. In addition, looking for ways to prevent or treat Alzheimer’s by studying people with the rare early onset familial form of Alzheimer’s might not be useful. These patients inherit genetic variations that alter the way beta amyloid is processed, but their illness is not really the same as most Alzheimer’s, Dr. Castellani and colleagues write. Two such efforts are DIAN and the Alzheimer’s Prevention Initiative described in a recent New York Timesarticle.
Finally, if the amyloid hypothesis is wrong, then new brain scans that can measure amounts of amyloid aren’t useful, and in fact may falsely diagnose someone with Alzheimer’s. This would make efforts to detect “preclinical Alzheimer’s disease” difficult.
If Not Amyloid, Then What?
So if the amyloid hypothesis is wrong, where should Alzheimer’s scientists focus? Dr. Castellani argues for starting over with a much broader approach. “I think we have to throw the kitchen sink at the problem,” he says. “Everything should be on the table, including a poly-therapy approach that encompasses multiple constructs and hypotheses.”
Starting over sounds discouraging, but Dr. Castellani seems confident that scientists will eventually find the cause of Alzheimer’s, if only because of a lucky break. “The proof will be in the pudding,” he says. “Sooner or later, there will be a breakthrough, and it will be by accident. At that point, the time and effort will be devoted to elucidating a mechanism that explains the accident, as the change in accepted science will have occurred by the force of empiricism.”
Dr. Castellani and his co-authors are not alone in their thinking. In the five years I’ve been blogging, many researchers have privately told me they think the amyloid hypothesis is wrong and that Alzheimer’s research is headed in the wrong direction. In the last couple of years, this discussion has become more open at research and public events (a webcast event at the University of Pennsylvania and ICAD 2008, for example). So why is the amyloid hypothesis still the main theory in Alzheimer’s research?
“Based on my interaction with various neuroscientists and clinicians in the field, the dominant hypothesis -- the so-called amyloid cascade, now the synaptic abeta hypothesis -- is widely viewed as seriously flawed,” says Dr. Castellani. “Unfortunately, there is a lot of money and associated influence, as well as prestigious names and titles with a personal stake in the ultimate success of treatment efforts modeled after their preferred construct. Alzheimer’s research involves selling ideas as much as (and more in my view) objective pursuit of knowledge. In this respect, the peer review process is a bit of a farce, as it encourages fealty to existing ideas and hampers innovation, in spite of unending lip service paid to the latter.”
And if there are doubts about the amyloid hypothesis, why do presentations and articles about Alzheimer’s for a lay audience often present it as fact? “The popular press (major media outlets, many of them) will run articles, with or without schematic representations, along with quotes from esteemed researchers at the world’s top institutions,” says Dr. Castellani. “They speak of (overly simplistic) removal of bad proteins, the exciting results from (hopelessly irrelevant) experimental models, economic burdens to society if something isn’t done, anecdotal accounts of human intervention, etc, etc. All this, which taken together amounts to no more than snake oil in terms of a cure, permeates public thought and pretty soon everyone wants to be vaccinated [against beta amyloid]. Lost in the process is a hypothesis that is deeply flawed and certainly unproven.”
A Lot at Stake
The amyloid hypothesis, right or wrong, is important because a large number of potential Alzheimer’s treatments are based on it. If it’s wrong, the hopes of patients and families will continue to be dashed, and millions of dollars will have been wasted on drug development. [It seems ironic that the cash prize associated with the award Dr. Castellani received is sponsored by Elan Pharmaceuticals, which is developing potential Alzheimer’s treatments based on the amyloid hypothesis.]
If it’s wrong, people enrolled in clinical trials of amyloid-lowering treatments are being subjected to unnecessary risk. In addition, looking for ways to prevent or treat Alzheimer’s by studying people with the rare early onset familial form of Alzheimer’s might not be useful. These patients inherit genetic variations that alter the way beta amyloid is processed, but their illness is not really the same as most Alzheimer’s, Dr. Castellani and colleagues write. Two such efforts are DIAN and the Alzheimer’s Prevention Initiative described in a recent New York Timesarticle.
Finally, if the amyloid hypothesis is wrong, then new brain scans that can measure amounts of amyloid aren’t useful, and in fact may falsely diagnose someone with Alzheimer’s. This would make efforts to detect “preclinical Alzheimer’s disease” difficult.
If Not Amyloid, Then What?
So if the amyloid hypothesis is wrong, where should Alzheimer’s scientists focus? Dr. Castellani argues for starting over with a much broader approach. “I think we have to throw the kitchen sink at the problem,” he says. “Everything should be on the table, including a poly-therapy approach that encompasses multiple constructs and hypotheses.”
Starting over sounds discouraging, but Dr. Castellani seems confident that scientists will eventually find the cause of Alzheimer’s, if only because of a lucky break. “The proof will be in the pudding,” he says. “Sooner or later, there will be a breakthrough, and it will be by accident. At that point, the time and effort will be devoted to elucidating a mechanism that explains the accident, as the change in accepted science will have occurred by the force of empiricism.”
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