Skin Cancer Linked to Lower AD Risk—But Don't Hit the Beach Just Yet

Skin cancer, a common and typically curable malignancy, may carry a fringe benefit—protection from Alzheimer’s disease. A longitudinal study of older adults in New York found that people were 79 percent less likely to develop AD if they had a history of non-melanoma skin cancer. Led by corresponding author Richard Lipton and senior author Joshua Steinerman of Albert Einstein College of Medicine in New York, the research was published online May 15 in Neurology. The findings add to growing evidence linking cancer to reduced risk of AD and other brain disorders (see review by Tabarés-Seisdedos and Rubenstein, 2013). However, before you grab that swimsuit and head to the beach, it may not be the skin cancer, per se, that protects, but an underlying genetic or metabolic susceptibility to it, researchers say. That would be consistent with molecular and clinical data attributing skin tumors to inactivation of enzymes needed for amyloid-β production.

Earlier research lent statistical weight to the curious observation that cancer patients rarely develop AD, and vice versa (Roe et al., 2005; Driver et al., 2012). Analyses confirmed the protection and showed it may be specific for AD, as the benefit did not extend to vascular dementia (ARF related news story on Roe et al., 2010). In the current study, first author Robert White and colleagues looked at the other side of the coin—the type of cancer that protects. They found that skin cancer in particular reduces the risk for AD.

The researchers studied 1,102 dementia-free seniors with or without a history of skin cancer, watching for mental decline in annual follow-up visits over the next three to four years. Based on questionnaires and medical tests, 141 people (12.8 percent) either reported a history of non-melanoma skin cancer (NMSC) or developed it during the study, while 961 remained NMSC-free. For 76 participants, plummeting scores on neuropsychological tests warranted a “probable or possible AD” diagnosis—yet only two (2.6 percent) of these individuals had NMSC.

Even after accounting for gender, education, demographics, and other AD risk factors, the scientists found NMSC associated with reduced AD risk. When they adjusted for the number of alleles of apolipoprotein E4, the top genetic risk factor for sporadic AD, the effect remained strong but lost statistical significance, possibly because only 769 of 1,102 participants were genotyped. The association between NMSC and reduced AD risk weakened when the researchers considered those who developed mixed AD/vascular dementia and other dementias. This suggests that NMSC’s protective effect may be specific to AD.

The strength of the protection surprised the researchers. That AD risk was reduced 79 percent in people with NMSC was “shocking to me,” Lipton told Alzforum. “It’s a very large reduction.”

Eric Larson of Group Health Research Institute, Seattle, Washington, found the figure “unusually large” and wonders if the results would hold up in a larger study. He noted that the confidence intervals are wide and the statistical significance borderline, presumably because the skin cancer group comprised just 12.8 percent of the total sample.

Nevertheless, the results echo earlier work by Cathy Roe and colleagues at Washington University School of Medicine in St. Louis, Missouri. The WashU analysis found that people with AD had reduced cancer risk compared to non-demented elderly. That protection was stronger for skin cancer than for other cancers, Roe said.

Though scientists have not clearly determined the molecular mechanisms underlying these epidemiological data, some consider γ-secretase a key candidate. AD researchers know this enzymatic complex for its critical role in cleaving amyloid precursor protein (APP) to produce the Aβ peptides that accumulate in the brains of people with AD. However, γ-secretase activates other pathways that mediate tumor suppression. Work by Huaxi Xu and colleagues at Sanford-Burnham Medical Research Institute, La Jolla, California, suggests the intracellular chunk of APP produced by γ-secretase cleavage curbs transcription of epidermal growth factor receptor (EGFR), which is upregulated in various cancers including NMSC (Zhang et al., 2007). In a similar vein, other researchers found unusually high EGFR expression in skin cells of mice lacking the γ-secretase component nicastrin (Li et al., 2007). In addition, recent work by Chinese scientists traced a rare skin disease to loss-of-function γ-secretase mutations (ARF related news story on Wang et al., 2010).

Consistent with these data, skin tumors develop in mice that lack γ-secretase’s catalytic component, presenilin (Xia et al., 2001), and AD patients treated with a γ-secretase inhibitor had increased skin cancer rates than untreated participants in a halted clinical trial (see Cummings, 2010; ARF related news story).

Based on his new data and previous work on cancer and AD, Lipton thinks some people may have a biological disposition to cancer that protects against AD. “In neurodegenerative diseases, specific populations of cells die, and that gives rise to cognitive impairment. In cancer, specific cell populations fail to stop dividing, and this causes a tumor,” he said. “One possibility is that developing skin cancer is a marker for a propensity for cells to divide, and that somehow is protective against AD.” Consistent with this idea, a recent WashU study suggests that susceptibility to apoptosis may underlie the inverse correlation between cancer and AD rates. The scientists report that lymphocytes from people with AD succumbed to apoptosis more easily than those from cancer patients (Behrens et al., 2012).

To more clearly delineate the biological mechanisms responsible for AD risk reduction conferred by skin cancer, Xu suggested collecting tissue from skin cancer patients and looking for changes in tumor-promoting molecules and pathways.—Esther Landhuis

Comments

    • User Profile Image Huaxi Xu
      Molecular Neurodegeneration
    • Posted:

    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. Epub 2009 Dec 23 PubMed.

    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. PubMed.

    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 PubMed.

    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. PubMed.

    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. PubMed.

    View all comments by Huaxi Xu

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References

News Citations

  1. Research Brief: Epidemiological Study Links Cancer, AD
  2. Research Brief: Did γ-Secretase Mutation Get Under Karl Marx’s Skin?
  3. Lilly Halts IDENTITY Trials as Patients Worsen on Secretase Inhibitor

Paper Citations

  1. Tabarés-Seisdedos R, Rubenstein JL. Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders. Nat Rev Neurosci. 2013 Apr;14(4):293-304. PubMed.
  2. Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC. Alzheimer disease and cancer. Neurology. 2005 Mar 8;64(5):895-8. PubMed.
  3. Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S, Wolf PA. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ. 2012 Mar 12;344:e1442. PubMed.
  4. 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.
  5. 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. PubMed.
  6. 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 PubMed.
  7. Wang B, Yang W, Wen W, Sun J, Su B, Liu B, Ma D, Lv D, Wen Y, Qu T, Chen M, Sun M, Shen Y, Zhang X. Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. PubMed.
  8. 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. PubMed.
  9. Cummings J. What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease?. Biol Psychiatry. 2010 Nov 15;68(10):876-8. PubMed.
  10. Behrens MI, Silva M, Salech F, Ponce DP, Merino D, Sinning M, Xiong C, Roe CM, Quest AF. Inverse Susceptibility to Oxidative Death of Lymphocytes Obtained From Alzheimer's Patients and Skin Cancer Survivors: Increased Apoptosis in Alzheimer's and Reduced Necrosis in Cancer. J Gerontol A Biol Sci Med Sci. 2012 Feb 24; PubMed.

External Citations

  1. apolipoprotein E4

Further Reading

Papers

  1. Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC. Alzheimer disease and cancer. Neurology. 2005 Mar 8;64(5):895-8. PubMed.
  2. 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.
  3. Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, Kurth T, Kiel DP, Lu KP, Seshadri S, Wolf PA. Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ. 2012 Mar 12;344:e1442. PubMed.
  4. Tabarés-Seisdedos R, Rubenstein JL. Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders. Nat Rev Neurosci. 2013 Apr;14(4):293-304. PubMed.

Primary Papers

  1. 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. PubMed.

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