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...  Read more

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

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...  Read more

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:
Bajic VP, Spremo-Potparevic B, Zivkovic L, Bonda DJ, Siedlak SL, Casadesus G, Lee HG, Smith MA (2009) The X-chromosome instability phenotype in Alzheimer's disease: A clinical sign of accelerating aging? Med Hypotheses. Abstract

Bajic VP, Spremo-Potparevic B, Zivkovic L, Djelic N, Smith MA (2008) Is the time dimension of the cell cycle re-entry in AD regulated by centromere cohesion dynamics? Biosci Hypotheses 1(3): 156-161. Abstract

Lee HG, Casadesus G, Nunomura A, Zhu X, Castellani RJ, Richardson SL, Perry G, Felsher DW, Petersen RB, Smith MA (2009a) The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse. Am J Pathol 174(3): 891-7. Abstract

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 (2009b) Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure. PLoS One 4(9): e7172. Abstract

McShea A, Harris PL, Webster KR, Wahl AF, Smith MA (1997) Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer's disease. Am J Pathol 150(6): 1933-9. Abstract

McShea A, Lee HG, Petersen RB, Casadesus G, Vincent I, Linford NJ, Funk JO, Shapiro RA, Smith MA (2007) Neuronal cell cycle re-entry mediates Alzheimer disease-type changes. Biochim Biophys Acta 1772(4): 467-72. Abstract

McShea A, Zelasko DA, Gerst JL, Smith MA (1999) Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli. Brain Res 815(2): 237-42. Abstract

Perry G, Roder H, Nunomura A, Takeda A, Friedlich AL, Zhu X, Raina AK, Holbrook N, Siedlak SL, Harris PL, Smith MA (1999) Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation. Neuroreport 10(11): 2411-5. Abstract

Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA (2001) Abortive apoptosis in Alzheimer's disease. Acta Neuropathol (Berl) 101(4): 305-10. Abstract

Roe CM, Fitzpatrick AL, Xiong C, Sieh W, Kuller L, Miller JP, Williams MM, Kopan R, Behrens MI, Morris JC (2010) Cancer linked to Alzheimer disease but not vascular dementia. Neurology 74(2): 106-12. Abstract

Spremo-Potparevic B, Zivkovic L, Djelic N, Plecas-Solarovic B, Smith MA, Bajic V (2008) Premature centromere division of the X chromosome in neurons in Alzheimer's disease. J Neurochem 106(5): 2218-23. Abstract

Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry G, Smith MA (2001) Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the 'two hit' hypothesis. Mech Ageing Dev 123(1): 39-46. Abstract

Zhu X, Lee HG, Perry G, Smith MA (2007) Alzheimer disease, the two-hit hypothesis: an update. Biochim Biophys Acta 1772(4): 494-502. Abstract

Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 3(4): 219-26. Abstract

Zhu X, Raina AK, Perry G, Smith MA (2006) Apoptosis in Alzheimer disease: a mathematical improbability. Curr Alzheimer Res 3(4): 393-6. Abstract

Zhu X, Siedlak SL, Wang Y, Perry G, Castellani RJ, Cohen ML, Smith MA (2008) Neuronal binucleation in Alzheimer disease hippocampus. Neuropathol Appl Neurobiol 34: 457-465. Abstract

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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:
1. Could Hyponatremia Be the Root Cause of Alzheimer's?

View all comments by Gregory Marlow

In this paper, the authors carried out an epidemiological study to explore the association between non-melanoma skin cancer (NMSC) and Alzheimer's disease (AD). From data on over 1,000 NMSC patients, the authors found that NMSC is associated with a reduced risk of "only AD" (probable or possible AD as the sole diagnosis) but not with that of a more mixed AD diagnosis (probable AD or possible AD, as well as mixed AD/vascular dementia) or all-cause dementia. The results of this study are consistent with a previous one which found that, at least in white, older adults, the prevalent AD was longitudinally associated with a reduced risk of cancer, while a history of cancer was associated with a reduced risk of AD (Roe et al., 2010).

These studies demonstrate that there may be molecular pathways that influence both AD and cancer in some manner. As the correlation only occurs between cancer and "only AD," it would be reasonable to assume that core AD factors (such as APP, BACE1, and γ-secretase that are directly associated with AD) might participate in these molecular pathways....  Read more

In this paper, the authors carried out an epidemiological study to explore the association between non-melanoma skin cancer (NMSC) and Alzheimer's disease (AD). From data on over 1,000 NMSC patients, the authors found that NMSC is associated with a reduced risk of "only AD" (probable or possible AD as the sole diagnosis) but not with that of a more mixed AD diagnosis (probable AD or possible AD, as well as mixed AD/vascular dementia) or all-cause dementia. The results of this study are consistent with a previous one which found that, at least in white, older adults, the prevalent AD was longitudinally associated with a reduced risk of cancer, while a history of cancer was associated with a reduced risk of AD (Roe et al., 2010).

These studies demonstrate that there may be molecular pathways that influence both AD and cancer in some manner. As the correlation only occurs between cancer and "only AD," it would be reasonable to assume that core AD factors (such as APP, BACE1, and γ-secretase that are directly associated with AD) might participate in these molecular pathways. Indeed, we and others have shown that a deficiency in γ-secretase results in increased skin tumorigenesis in mice, though the proposed mechanisms were different: We found that a loss of γ-secretase activity due to presenilin deletion led to reduced generation of APP intracellular domain (AICD), which can negatively regulate the expression of EGFR, an important player in tumorigenesis (Zhang et al., 2007). Another study (Li et al., 2007) also found that a loss of γ-secretase activity due to nicastrin deletion resulted in abnormal EGFR and Notch signaling pathways. Additionally, other studies have shown that presenilin 1 can be a negative regulator of the Wnt/β-catenin signaling pathway (Xia et al., 2001; Kang et al., 2002). Nevertheless, all studies indicate that PS/γ-secretase is a key player linking AD and cancer. In support of this, Eli Lilly’s semagacestat clinical trial of γ-secretase inhibitor for treating AD has failed, with some recipients developing skin cancers.

References:
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. Abstract

Zhang YW, Wang R, Liu Q, Zhang H, Liao FF, Xu H. Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10613-8. Abstract

Li T, Wen H, Brayton C, Das P, Smithson LA, Fauq A, Fan X, Crain BJ, Price DL, Golde TE, Eberhart CG, Wong PC. Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase. J Biol Chem. 2007 Nov 2;282(44):32264-73. Abstract

Xia X, Qian S, Soriano S, Wu Y, Fletcher AM, Wang XJ, Koo EH, Wu X, Zheng H. Loss of presenilin 1 is associated with enhanced beta-catenin signaling and skin tumorigenesis. Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10863-8. Abstract

Kang DE, Soriano S, Xia X, Eberhart CG, De Strooper B, Zheng H, Koo EH. Presenilin couples the paired phosphorylation of beta-catenin independent of axin: implications for beta-catenin activation in tumorigenesis. Cell. 2002 Sep 20;110(6):751-62. Abstract

View all comments by Huaxi Xu