The article by Roe et al. is a strong contribution to the literature of two fields—cancer and AD. But while the field will benefit from having access to the data and the analyses reported, the article and the accompanying editorial bring up two questions in my mind.
The first is a solely theoretical one. In their accompanying tables, the authors cite the ApoE profiles of the two groups (those getting cancer and those getting dementia) but unfortunately do not comment on the data itself. This is frustrating, because the strong correlation between carrying one or two ApoE4 alleles and elevated AD risk means a potential insight into mechanism has slipped through their fingers. The sample size is large enough that they should replicate the often-observed AD/ApoE4 connection in their dementia population. But then, according to their hypothesis, the cancer data should go the other way, i.e., ApoE4 genotype should be protective. The 4/4 numbers are small, but seem adequate given that increased risk of AD for this group has been estimated to be above 10-fold. I don't see this effect in the paper’s cancer table, although I do see it (in the expected direction) in the dementia table. If my cursory impression is true, and there is no ApoE4-cancer linkage, it would hint that the cancer/AD connection is working off a parallel biological mechanism that is independent of the ApoE mechanism. And since it is widely believed that ApoE cannot account for all cases of sporadic AD, this could be a very important insight.
My second comment is both theoretical and personal. On behalf of the many laboratories (Herrup, Arendt, Davies, Lamb, Neve, Copani, Chun, Slack, Park, Potter, Greene, Benes, Dawson, Julien, Bowser, Sharp, Rakic, Smith and Perry, and probably others) that have labored hard over the past 15 years to repeatedly demonstrate the linkage between loss of cell cycle control in adult nerve cells and the onset of neurodegeneration in AD and other diseases, I wish to express our concern that neither the authors of the study nor the writers of the editorial mentioned this rapidly growing body of work and how it relates to their findings. In bringing up Pin1, which is more closely associated with DNA damage than with cell cycle regulation, they also ignore the excellent work on the association between mutations in DNA repair enzymes and developmental nerve cell death (e.g., ATM, ATR, Mre11, Nbs1, etc.). I mention this partly out of personal pride, but mostly because it raises a potentially important theoretical question about mechanism. In every case, DNA damage and/or loss of nerve cell cycle control is associated with increased nerve cell death. Therefore, on first principles we might expect that the correlation between AD and cancer (also accompanied by DNA damage and a loss of cell cycle control) would be positive, not negative as reported here. Even putting aside my obvious personal interest, I suggest that the lack of discussion of this point by the authors is an opportunity missed.
One molecular mechanism that could explain this is sodium. In the Hypothesis Factory (1) I explain how repeated osmotic swelling of the brain resulting from hyponatremia could be a root cause of Alzheimer’s. It is widely believed that a high-salt diet is somehow responsible for a higher rate of stomach cancer. This may explain why the Japanese have a higher rate of stomach cancer coincident with a lower rate of Alzheimer’s.
Comments
Rutgers University
The article by Roe et al. is a strong contribution to the literature of two fields—cancer and AD. But while the field will benefit from having access to the data and the analyses reported, the article and the accompanying editorial bring up two questions in my mind.
The first is a solely theoretical one. In their accompanying tables, the authors cite the ApoE profiles of the two groups (those getting cancer and those getting dementia) but unfortunately do not comment on the data itself. This is frustrating, because the strong correlation between carrying one or two ApoE4 alleles and elevated AD risk means a potential insight into mechanism has slipped through their fingers. The sample size is large enough that they should replicate the often-observed AD/ApoE4 connection in their dementia population. But then, according to their hypothesis, the cancer data should go the other way, i.e., ApoE4 genotype should be protective. The 4/4 numbers are small, but seem adequate given that increased risk of AD for this group has been estimated to be above 10-fold. I don't see this effect in the paper’s cancer table, although I do see it (in the expected direction) in the dementia table. If my cursory impression is true, and there is no ApoE4-cancer linkage, it would hint that the cancer/AD connection is working off a parallel biological mechanism that is independent of the ApoE mechanism. And since it is widely believed that ApoE cannot account for all cases of sporadic AD, this could be a very important insight.
My second comment is both theoretical and personal. On behalf of the many laboratories (Herrup, Arendt, Davies, Lamb, Neve, Copani, Chun, Slack, Park, Potter, Greene, Benes, Dawson, Julien, Bowser, Sharp, Rakic, Smith and Perry, and probably others) that have labored hard over the past 15 years to repeatedly demonstrate the linkage between loss of cell cycle control in adult nerve cells and the onset of neurodegeneration in AD and other diseases, I wish to express our concern that neither the authors of the study nor the writers of the editorial mentioned this rapidly growing body of work and how it relates to their findings. In bringing up Pin1, which is more closely associated with DNA damage than with cell cycle regulation, they also ignore the excellent work on the association between mutations in DNA repair enzymes and developmental nerve cell death (e.g., ATM, ATR, Mre11, Nbs1, etc.). I mention this partly out of personal pride, but mostly because it raises a potentially important theoretical question about mechanism. In every case, DNA damage and/or loss of nerve cell cycle control is associated with increased nerve cell death. Therefore, on first principles we might expect that the correlation between AD and cancer (also accompanied by DNA damage and a loss of cell cycle control) would be positive, not negative as reported here. Even putting aside my obvious personal interest, I suggest that the lack of discussion of this point by the authors is an opportunity missed.
View all comments by Karl Herrup�
One molecular mechanism that could explain this is sodium. In the Hypothesis Factory (1) I explain how repeated osmotic swelling of the brain resulting from hyponatremia could be a root cause of Alzheimer’s. It is widely believed that a high-salt diet is somehow responsible for a higher rate of stomach cancer. This may explain why the Japanese have a higher rate of stomach cancer coincident with a lower rate of Alzheimer’s.
References:
View all comments by Gregory Marlow1. Could Hyponatremia Be the Root Cause of Alzheimer's?
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