The Association Between Alzheimer's Disease and Cancer
Several studies have reported an inverse association between cancer and Alzheimer's disease, such that cancer survivors had a decreased risk of developing Alzheimer's disease and people with Alzheimer's disease were at lower risk of developing cancer.
Previous studies for establishing relationship between neurodegenerative diseases such as Huntington's disease, Parkinson’s disease and cancer suggested the existence of an inverse association between the diseases. This makes it more important to establish the association between cancer and Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes problems with memory and thinking. It is most common cause of dementia (memory loss) in older people. Cancer is a group of diseases with uncontrolled division of abnormal cells which may invade to other organs in the body. Both the diseases are life threatening.
Various biologic mechanisms have been hypothesised to underlie the inverse association between the two diseases.
Inefficient cell division in neurons of people with AD leads to efficient cell death due to cellular cellular aging subjected to apoptosis (programmed cell death that occurs when the normal cell is damaged and it needs to be removed) (Vincent I et al., 1996). This process in dementia of AD is complementary to cancer and may provide biological explanation for the inverse relationship in the incidence of cancer and AD (Copani A et al., 2007).
Studies Supporting the Concept of Inverse Association
- A research carried out in a cancer population since its entry into Framingham Heart Study, related cancer with risk of incident AD and estimated the risk of incident cancer among participants with or without AD. The study evaluated 1,278 patients with or without history of cancer aged 65 or more and free of dementia at base-line (1986-90). Over a mean follow-up of 10 years the study concluded that, cancer survivors had a lower risk of AD than those without cancer and patients with AD had a lower risk of incident cancer.
- Another population-based incident study reported that risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced.
Factors Contributing to the Inverse Relation of AD and Cancer
According to a systemic review by S. Ovais, several factors that are known to be upregulated in any type of cancer to sustain growth and survival of cells, are down regulated in AD leading to neuronal degeneration.
Some of these factors include
1. p53: p53 is responsible to start apoptosis if DNA damage is found to be irreparable. Activation of p53 leads to cell cycle arrest followed by induced apoptosis of the damaged cell. Upregulation of p53 leads to increased risk of Alzheimer's due to massive neuronal death which represents an important pathological hallmark of Alzheimer's. Whereas down regulation or deletion of p53 leads to cancer.
2. Estrogen: Estrogen is neuroprotective hormone. It even protects neurons from hypoglycaemic, ischemic injuries and oxidative stress.
In AD an imbalance occurs between neuronal injury and repair. Role of estrogen in reducing the risk of AD is established. And role of estrogen in increased risk of ovarian, endometrial and breast cancer is also well-known.
3. Similar to estrogen, Neurotrophins and growth factors (NGF) are neuroprotective and involved in regulation of tumor growth and cancer progression. Additionally, interactions of neurotrophic factors and glutamate are involved in regulating developmental and adult neuroplasticity lowering the risk of development of AD.
4. Epidermal growth factor receptor (EGFR) is involved in growth, proliferation and survival of cells. Deficiency of EGFR is seen in AD and it's overexpression is involved in Cancer.
5. cAMP: cAMP provides survival signals for the neurons reducing the risk of AD. Whereas it contributes to tumor progression.
6. Bcl-2 and other oncogenes contributed to cancer cell survival, there overexpression provides protection against cell death induced by β amyloid. These oncogenes are down-regulated in AD and over expressed in cancer.
7. PI3K/AKT/mTOR pathway reduce apoptosis and promotes proliferation. There is over activation of this pathway in cancer. It is neuroprotective pathway.
TGF-β, TNF-α, IGF-1, Telomerase, ROS and many other factors point towards the inverse association of the two life-threatening diseases.
Interestingly, all those factors that contribute to cell growth and proliferation are increased in cancer and decreased in AD. However, there are many pathways that are common in both diseases that operate similarly and are not altered by disease process.
Does this conclude that the inverse association is actually present?
Establishing the link between age related diseases is complex and several issues must be dealt with before concluding that this association is true.
Another research conducted in more than 0.7 million cancer cases of Medicare patients residing within the population based Surveillance, epidemiology and end-results (SEER) program, examined risk of incident cancer after AD diagnosis, as well as risk of first AD diagnosis in cancer survivors. The study did not support the association of these diseases.
The confounding issues with the previous studies
• It could be that, Cancer survivors might have reduced risk of developing Alzheimer's, simply because they are more likely to die even before they can develop it.
• Severe cognitive impairment might lead to reduced screening and diagnosis of cancer due to less reporting.
• Existence of one disease might hide the diagnosis of other, because any new finding in patients with AD or cancer would be misinterpreted as a cause of primary disease which was first diagnosed.
• Cognitive decline due to neurodegeneration as in AD may be wrongly interpreted as an adverse effect of chemotherapy in cancer patients. (Hutchinson AD et al., 2012)
Further work is needed to prove the link between the two diseases which might be helpful in understanding the potential impact of cancer treatment on risk of Alzheimer's disease.
Currently there is no drug established to treat AD. However, cholinesterase inhibitors and memantine are approved by FDA for treating cognitive symptoms. Study of regulatory factors and their relation in both groups of diseases might help in developing new effective drugs for AD.
Are you familiar with an Alzheimer's patient who is a cancer survivor?
1. Shafi, O. (2016). Inverse relationship between Alzheimer’s disease and cancer, and other factors contributing to Alzheimer’s disease: a systematic review. BMC Neurology, 16, 236. http://doi.org/10.1186/s12883-016-0765-2
2. Bajaj, A., Driver, J.A. & Schernhammer, E.S. Cancer Causes Control (2010) 21: 697. https://doi.org/10.1007/s10552-009-9497-6
3. Driver Jane A, Beiser Alexa, AuRhoda, Kreger Bernard E, Splansky Greta Lee, Kurth Tobiaset al. (2012) Inverse association between cancer and Alzheimer’s disease: results from the Framingham Heart Study. BMJ ; 344:e1442
4. Massimo Musicco, Fulvio Adorni, Simona Di Santo, Federica Prinelli, Carla Pettenati, Carlo Caltagirone et al., (2013) Inverse occurrence of cancer and Alzheimer disease Neurology Jul, 81 (4) 322-328
5. Sørensen SA, Fenger K, Olsen JH. (1999). Significantly lower incidence of cancer among patients with Huntington disease: an apoptotic effect of an expanded polyglutamine tract? Cancer. 86(7):1342–6.
© 2018 Sherry Haynes