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

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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