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.