White RS, Lipton RB, Hall CB, Steinerman JR.
Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk.
Neurology. 2013 May 21;80(21):1966-72.
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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.
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.
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.
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. Epub 2007 Sep 7
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.
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.
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