Roe CM, Fitzpatrick AL, Xiong C, Sieh W, Kuller L, Miller JP, Williams MM, Kopan R, Behrens MI, Morris JC. Cancer linked to Alzheimer disease but not vascular dementia. Neurology. 2010 Jan 12;74(2):106-12. Epub 2009 Dec 23 PubMed.
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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 HerrupCase Western Reserve University
Comment by Hyoung-gon Lee, Xiongwei Zhu, Xinglong Wang, Rudy J. Castellani, George Perry, and Mark A. Smith
Cancer, Alzheimer Disease, and Cardiovascular Disease: Associations and Disassociations—Clues to Etiology?
There are numerous pathological similarities between cancer and Alzheimer disease (AD), including, but not limited to, loss of cell cycle control (McShea et al., 1997), DNA instability/replication (Bajic et al., 2008; Spremo-Potparevic et al., 2008; Zhu et al., 2008; Bajic et al., 2009), abnormal proliferative signal transduction pathways (McShea et al., 1999; Perry et al., 1999), and avoidance of apoptosis (Raina et al., 2001; Zhu et al., 2006). Additionally, it is notable that numerous features of AD follow the oncogenic stimulation of neurons either in vitro (McShea et al., 2007) or in vivo (Lee et al., 2009a). Given such striking similarities, it is perhaps surprising that AD is associated with a reduced risk of cancer and, likewise, that cancer was associated with a reduced risk of AD (Roe et al., 2010). However, since it is clear that the etiologies of both AD and cancer are likely multifactorial and involve a series of “hits” (Zhu et al., 2001; Zhu et al., 2004; Zhu et al., 2007), one possible explanation is that the risk factors predisposing to cancer are protective against AD and, conversely, that the risk factors for AD are protective against cancer. In this regard, it is worth noting that the etiopathogenesis of cancer involves stem cells and perhaps other somatic cell types that have proliferative potential, whereas AD affects neurons that are terminally differentiated. Supporting such an association, cardiomyopathy and heart disease are associated with an increased risk of AD and are conditions associated with another terminally differentiated cell, the cardiomyocyte (Lee et al., 2009b). Obviously, such associations and disassociations might provide clues to etiology.
References:
Bajić VP, Spremo-Potparević B, Zivković L, Bonda DJ, Siedlak SL, Casadesus G, Lee HG, Smith MA. The X-chromosome instability phenotype in Alzheimer's disease: a clinical sign of accelerating aging?. Med Hypotheses. 2009 Dec;73(6):917-20. PubMed.
Bajić VP, Spremo-Potparević B, Zivković L, Djelić N, Smith MA. Is the time dimension of the cell cycle re-entry in AD regulated by centromere cohesion dynamics?. Biosci Hypotheses. 2008;1(3):156-161. PubMed.
Lee HG, Casadesus G, Nunomura A, Zhu X, Castellani RJ, Richardson SL, Perry G, Felsher DW, Petersen RB, Smith MA. The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse. Am J Pathol. 2009 Mar;174(3):891-7. PubMed.
Lee HG, Chen Q, Wolfram JA, Richardson SL, Liner A, Siedlak SL, Zhu X, Ziats NP, Fujioka H, Felsher DW, Castellani RJ, Valencik ML, McDonald JA, Hoit BD, Lesnefsky EJ, Smith MA. Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure. PLoS One. 2009;4(9):e7172. PubMed.
McShea A, Harris PL, Webster KR, Wahl AF, Smith MA. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol. 1997 Jun;150(6):1933-9. PubMed.
McShea A, Lee HG, Petersen RB, Casadesus G, Vincent I, Linford NJ, Funk JO, Shapiro RA, Smith MA. Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta. 2007 Apr;1772(4):467-72. PubMed.
McShea A, Zelasko DA, Gerst JL, Smith MA. Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli. Brain Res. 1999 Jan 9;815(2):237-42. PubMed.
Perry G, Roder H, Nunomura A, Takeda A, Friedlich AL, Zhu X, Raina AK, Holbrook N, Siedlak SL, Harris PL, Smith MA. Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. Neuroreport. 1999 Aug 2;10(11):2411-5. PubMed.
Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA. Abortive apoptosis in Alzheimer's disease. Acta Neuropathol. 2001 Apr;101(4):305-10. PubMed.
Roe CM, Fitzpatrick AL, Xiong C, Sieh W, Kuller L, Miller JP, Williams MM, Kopan R, Behrens MI, Morris JC. Cancer linked to Alzheimer disease but not vascular dementia. Neurology. 2010 Jan 12;74(2):106-12. Epub 2009 Dec 23 PubMed.
Spremo-Potparević B, Zivković L, Djelić N, Plećas-Solarović B, Smith MA, Bajić V. Premature centromere division of the X chromosome in neurons in Alzheimer's disease. J Neurochem. 2008 Sep;106(5):2218-23. PubMed.
Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA. Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the 'two hit' hypothesis. Mech Ageing Dev. 2001 Dec;123(1):39-46. PubMed.
Zhu X, Lee HG, Perry G, Smith MA. Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta. 2007 Apr;1772(4):494-502. PubMed.
Zhu X, Raina AK, Perry G, Smith MA. Alzheimer's disease: the two-hit hypothesis. Lancet Neurol. 2004 Apr;3(4):219-26. PubMed.
Zhu X, Raina AK, Perry G, Smith MA. Apoptosis in Alzheimer disease: a mathematical improbability. Curr Alzheimer Res. 2006 Sep;3(4):393-6. PubMed.
Zhu X, Siedlak SL, Wang Y, Perry G, Castellani RJ, Cohen ML, Smith MA. Neuronal binucleation in Alzheimer disease hippocampus. Neuropathol Appl Neurobiol. 2008 Aug;34(4):457-65. PubMed.
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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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