Several studies have shown that Alzheimer’s patients appear to be less susceptible to cancer, but the mechanism behind this association remains mysterious. A study in the August 25 Journal of Neuroscience may provide some clues. Researchers led by Michael Mullan at the Roskamp Institute in Sarasota, Florida, sought to answer the question of whether the Alzheimer’s brain is fundamentally pro-angiogenic or anti-angiogenic. They implanted gliomas into the brains of two AD mouse models, and found less tumor growth and angiogenesis in these animals than in similarly treated wild-type mice, implying that on balance, these AD mouse brains were anti-angiogenic. The results may shed light not only on the apparent suppression of cancer in AD patients, but also on the complex relationship between AD and vascular factors.

Several studies have found that vascular damage can exacerbate AD (see, e.g., Snowdon et al., 1997 and Petrovich et al., 2000), perhaps by decreasing the clearance of Aβ across the blood-brain barrier (see ARF related news story on Bell et al., 2009). The main genetic risk factor for AD, ApoE4, is also a risk factor for cardiovascular conditions, and abnormalities in brain blood vessels are common in people with Alzheimer’s. AD brains contain elevated levels of several pro-angiogenic growth factors such as VEGF and bFGF, but they also contain anti-angiogenic factors such as endostatin (see Deininger et al., 2002). In previous work, Mullan and colleagues showed that soluble Aβ peptides themselves are anti-angiogenic (see Paris et al., 2004; Paris et al., 2005; Patel et al., 2008). Because of this mix of factors that promote and suppress blood vessel growth, it was not clear whether the AD brain was a favorable environment for angiogenesis, as some have speculated, or not.

To address this question, first author Daniel Paris implanted invasive GL261 murine gliomas, known to induce vascularization, into the right frontal lobes of AD mice expressing APP carrying the Swedish mutation (Tg2576), double transgenic mice carrying both APPswe and a presenilin-1 mutation (TgPS1/APPswe), and wild-type littermates. Tumors were allowed to grow for three weeks before analysis. Paris and colleagues found that tumor volumes were reduced by about half in the AD mice compared to wild-type, and that within the tumors, vascular density was also about half as much in the AD mice, indicating that vascularization and tumor growth were impaired. Paris and colleagues also showed in vitro that brain homogenates from the AD mice inhibited the formation of capillaries by human brain microvascular cells, both alone and in the presence of glioma cells. The results suggest that, at least in these mouse models, the AD brain is predominantly anti-angiogenic.

“This is a fascinating study,” suggested Cathy Roe of Washington University in St. Louis, Missouri, in an e-mail to ARF. Roe’s work has shown an inverse epidemiological link between Alzheimer’s and several types of cancer (see ARF related news story). “An amyloid-β-related mechanism that affects tumor growth and vascularization, as suggested by the results of Paris et al., would provide an explanation for an inverse relationship between AD and solid-tumor cancers at many sites,” she wrote (see full comment below).

Thomas Bayer, of the University of Göttingen in Germany, said that the tumor growth inhibition effects in this study appear robust, but noted there are some unanswered questions. The double-transgenic mouse model has a much higher level of Aβ in its brain than does the Tg2576 mouse, Bayer said, so it would be interesting to know why the double-transgenic does not show greater tumor inhibition than the Tg2576 mouse. Bayer said it will also be important to study the molecular mechanisms of how Aβ is able to interfere with vascular function.

The new findings help to flesh out the picture of AD, angiogenesis, and vascular insults, implying that not only does vascular damage contribute to AD neurodegeneration, but also that AD brains may be especially poorly equipped to repair such damage. In an e-mail to ARF, Paris wrote, “This may explain why vascular insults, such as a stroke, have particularly devastating effects in AD brains.” Their work also suggests, Paris wrote, that “Therapies stimulating brain vascularization may be beneficial in AD patients. We are developing different methodologies to stimulate angiogenesis in the brains of transgenic mouse models of AD, with the hope that certain of these approaches could be useful for the treatment of AD.”—Madolyn Bowman Rogers


  1. This is a fascinating study. I think the authors have made a convincing case that AD mice develop fewer, and smaller, gliomas compared to their wild-type littermates. Further, there was much less vascularization surrounding the tumors in the AD mice, suggesting that the slowed tumor growth was due to decreased angiogenesis in these mice. This was demonstrated using two strains of mice, which I believe lends further confidence in the results.

    I would be interested to see whether these results extend to solid tumors at other body sites. There is some preliminary epidemiological evidence that the development of cancer and AD may be inversely associated in humans, although there is much work to be done before concluding that such a relationship does indeed exist. A limitation of the work of our group in this area is that we were unable to examine associations between AD and cancer development by cancer type, given the low frequency of individual site-specific cancers. Therefore, we can only conclude that AD may be inversely associated with multiple cancer types. However, an amyloid-β-related mechanism that affects tumor growth and vascularization, as suggested by the results of Paris et al., would provide an explanation for an inverse relationship between AD and solid-tumor cancers at many sites.

    Interestingly, we also know that people with Down syndrome, who develop amyloid-β plaques at a young age, have a lower incidence of solid-tumor development compared to individuals without Down syndrome. Some research suggests that this may be due to decreased angiogenesis (Reynolds et al., 2010). In any case, Paris et al. are carrying out an exciting line of research, and I look forward to their next report.


    . Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome. Nature. 2010 Jun 10;465(7299):813-7. PubMed.

    View all comments by Cathy Roe
  2. In this paper, researchers report that GL261 murine glioma cells were implanted in the brains of six-month-old Tg APPswe, Tg PS1/APPswe, and wild-type littermate mice which were sacrificed after three weeks. At that age, Tg APPswe mice have elevated brain levels of Aβ but do not yet have Aβ plaques, in contrast to Tg PS1/APPswe mice, which have higher levels of Aβ and already develop Aβ plaques. Since both APP Tg mouse models also express full-length APP and other APP metabolites, it is not clear if Aβ is responsible for tumor growth inhibition. A good control would have been to compare the APPswe and Tg PS1/APPswe mice with a model overexpressing wild-type APP. It is puzzling that there is no dose-dependent effect of Aβ, the levels being higher in TgPS1/APPswe. Therefore, it would be very interesting to investigate if a loss of the trophic APP function (controlled by secreted APPα) is responsible for the effect in vivo.

    Maria Isabel Behrens, Corinne Lendon, John Morris, and Cathy Roe have previously pointed out a very interesting inverse relation between Alzheimer’s and cancer. They have demonstrated that “the presence of one disease was found to correlate with a reduced probability of subsequently diagnosing the other. This association was observed for dementia of the Alzheimer’s type, but not for vascular dementia, suggesting the existence of a common biological mechanism underlying neurodegenerative disorders and cancer” (1-3).

    We have recently found evidence supporting these findings (4). APP has an important function in the pathogenesis of pancreatic and colon cancer cell growth. A growing number of reports revealed full-length APP as a potential tumor marker, especially in prostate, pancreatic, melanoma, and oral squamous cell carcinoma. More than that, the rate of cancer-specific survival for patients with APP-positive tumors was significantly lower than those with APP-negative tumors. These studies are in good agreement with our findings that APP and secreted sAPPα are tightly involved in cancer development (5-8).

    We found that valproic acid, a histone deacetylase (HDAC) inhibitor downregulating APP and sAPPα in colon and pancreatic tumor cells, increased expression of GRP78 (an ER chaperone), known to bind APP. Thereby, APP maturation and transport was blocked, which is a prerequisite to generate sAPPα at the plasma membrane. Moreover, APP was found to be overexpressed only in malignant cells of tumor tissue from patients (4). Therefore, we strongly believe that the secreted form of APP (sAPP) has a dominant role in tumor growth activity.

    Serrano et al. used a different approach to study the connection between cancer and Alzheimer’s. They injected the carcinogen 20-methylcholanthrene in the brain of APPswe/PS1-A246E mice (9). Transgenic mice developed tumors faster and with higher incidence than their wild-type littermates. This finding is seemingly contradictory to the data by Paris et al. However, we believe that in both approaches the growth-promoting effect of APP cannot be ruled out in addition to a possible toxic function of Aβ.

    In addition, the suggested molecular mechanism for how Aβ could inhibit neo-angiogenesis and tumor growth needs further investigation.


    . Alzheimer disease and cancer. Neurology. 2005 Mar 8;64(5):895-8. PubMed.

    . Cancer linked to Alzheimer disease but not vascular dementia. Neurology. 2010 Jan 12;74(2):106-12. Epub 2009 Dec 23 PubMed.

    . A common biological mechanism in cancer and Alzheimer's disease?. Curr Alzheimer Res. 2009 Jun;6(3):196-204. PubMed.

    . Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 2010 Apr 2;285(14):10678-89. Epub 2010 Feb 9 PubMed.

    . Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res. 2003 Nov 1;63(21):7032-7. PubMed.

    . Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res. 2009 Jan 1;69(1):137-42. PubMed.

    . Increased expression of amyloid precursor protein in oral squamous cell carcinoma. Int J Cancer. 2004 Sep 20;111(5):727-32. PubMed.

    . Induction of terminal differentiation in melanoma cells on downregulation of beta-amyloid precursor protein. J Invest Dermatol. 2010 May;130(5):1400-10. PubMed.

    . High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease. Oncogene. 2010 Apr 15;29(15):2165-71. PubMed.

    View all comments by Vivek Venkataramani
  3. The Alzheimer's Disease and Cancer Relationship
    These results raise the question of whether amyloid-β peptides might be useful anti-cancer agents. It also adds further support to the idea that amyloid-β has differential effects on pluripotent/totipotent (e.g., Porayette et al., 2009) and differentiated (e.g., Liu et al., 2004) cell types.


    . Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells. J Biol Chem. 2009 Aug 28;284(35):23806-17. PubMed.

    . Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression. J Neurochem. 2004 Feb;88(3):554-63. PubMed.

    View all comments by Craig Atwood

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News Citations

  1. Paper Alert—Transcription Factors Regulate Aβ Clearance
  2. Research Brief: Epidemiological Study Links Cancer, AD

Paper Citations

  1. . Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997 Mar 12;277(10):813-7. PubMed.
  2. . Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging Study. Neurobiol Aging. 2000 Jan-Feb;21(1):57-62. PubMed.
  3. . SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol. 2009 Feb;11(2):143-53. PubMed.
  4. . Aberrant neuronal and paracellular deposition of endostatin in brains of patients with Alzheimer's disease. J Neurosci. 2002 Dec 15;22(24):10621-6. PubMed.
  5. . Inhibition of angiogenesis by Abeta peptides. Angiogenesis. 2004;7(1):75-85. PubMed.
  6. . Anti-angiogenic activity of the mutant Dutch A(beta) peptide on human brain microvascular endothelial cells. Brain Res Mol Brain Res. 2005 May 20;136(1-2):212-30. PubMed.
  7. . Potent anti-angiogenic motifs within the Alzheimer beta-amyloid peptide. Amyloid. 2008 Mar;15(1):5-19. PubMed.

Other Citations

  1. Tg2576

Further Reading

Primary Papers

  1. . Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease. J Neurosci. 2010 Aug 25;30(34):11251-8. PubMed.