Wwith age comes disease. Cancer and Alzheimer’s dementia are among the most common and feared health conditions – especially in countries with aging populations such as the UK. Several decades ago, researchers at a psychiatric center in New York observed a peculiar relationship between these two diseases. At autopsythey found an inverse relationship between cancer and Alzheimer’s disease.
In one of the first epidemiological studies on the subject, Jane Driver of Brigham and Women’s Hospital in Boston, Massachusetts in the USA followed 1,278 participants aged 65 and over for an average of 10 years. Published in 2012the results showed that cancer survivors had a 33% reduced risk of later developing Alzheimer’s disease compared to people without a history of cancer.
As intriguing as the finding was, the scientific community urged caution and pointed out potential pitfalls in dealing with age-related diseases. One of them dealt with a so-called survivorship bias: perhaps people with a history of cancer simply do not live long enough to develop Alzheimer’s disease.
Since then, scientists around the world have analyzed the link between cancer and Alzheimer’s disease in more detail, building an increasingly convincing case. In the largest study to datepublished in July this year, researchers at Imperial College London provide convincing evidence of a lower incidence of dementia after a cancer diagnosis. They looked at the NHS health data of more than three million people aged 60 and over and followed them for an average period of 9.3 years, taking extra care to correct for potential biases. Their results show that cancer survivors have a 25% lower risk of developing age-related dementia compared to people without a history of cancer. The inverse association was observed for the most common types of cancers such as prostate, colon, lung and breast.
“The relationship between cancer and Alzheimer’s disease is very intriguing and it’s persistent,” said Erin Abner, a professor at the University of Kentucky. “Many people have questioned the results and tried hard to find other explanations for the inverse association, but it just keeps showing up, even after confounding factors are taken into account.”
Two years ago Abner published clinical evidence for the inverse association. Unlike previous epidemiological studies, she looked at brain postmortems of patients at the University’s Alzheimer’s Research Center. “We found a fairly consistent association between someone who had cancer and having lower levels of amyloid pathology in their brain, which is a hallmark of Alzheimer’s disease,” she says.
In her study, the inverse association was only seen with Alzheimer’s disease and not with dementia in general. In contrast, many of the previous epidemiological studies did not distinguish between Alzheimer’s disease and other age-related dementias. However, the majority of elderly patients with dementia have Alzheimer’s.
But that is not the whole story; there is another twist to the inverse relationship. Not only do those with a history of cancer have a reduced risk of dementia, but those with Alzheimer’s disease are less likely to develop cancer. In her 2012 study, Jane Driver reported that the inverse relationship goes both ways, a finding that replicated in northern Italy looking at over one million residents, and more recently in South Korea. According to this studypatients with Alzheimer’s disease show a 37% lower probability of developing overall malignancy compared to those without dementia. Again, the finding was met with skepticism. Perhaps, critics argued, people with dementia were less likely to be screened for cancer given the potentially limited benefit of therapies.
“The results have been replicated again and again, and most experts in the field now believe that the reverse relationship appears to be real,” says Elio Riboli who led the study at Imperial College London that also confirmed the bidirectionality. “The next step is to understand the biology behind this phenomenon.”
Some researchers have suggested that cancer treatment itself may have an effect on dementia risk. In recent years, inflammation has emerged as a central process in the initiation and progression of Alzheimer’s disease, so it is possible that chemotherapy may protect neurons by suppressing inflammation.
But for Elio Riboli, this is not the whole story. The fact that the inverse relationship is bidirectional suggests that there may be underlying biological mechanisms that affect the two groups of diseases in opposite directions. The researchers at Imperial College carried out genetic analyses. “Looking at hundreds of genes, we identified a genetic profile that predicts an increased risk of cancer and we found that this profile is linked to a lower risk of dementia.”
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According to Riboli, the specific genetic factors may be involved in tissue regeneration. “Growth factors are a large family of molecules that regulate tissue renewal and growth. They are generally associated with better cardiovascular health,” he says. “Having a genetic makeup that favors replication allows for better renewal of tissues and arteries, but may also slightly increase the risk of some cancers.”
Surprising findings can open up new lines of research, says Riboli. For example, it has long been known that people with diabetes have an increased risk of developing cancer, with one notable exception: men with diabetes have a 10-20% reduced risk of developing prostate cancer. “Why do diabetics have a reduced risk of prostate cancer, a cancer for which we are desperately trying to understand the risk factors?” asked Riboli. Similarly, research into the inverse relationship between cancer and dementia may shed light on new molecular pathways that contribute to, or protect people from, the development of dementia. “You open a window and suddenly you see a new horizon,” he says.
Cancer is linked to uncontrolled cell growth, while dementia is linked to excessive neuronal death. Mikyoung Park of the Korea Institute of Science and Technology in Seoul, South Korea, recently published a revise of molecular mechanisms that work in reverse in cancer and neurodegeneration – some leading to increased resistance to cell death and others to a higher risk of cell death. Dysfunctional mitochondria, the cellular powerhouses, may provide an important link between cancer and neurodegeneration, a hypothesis presented a decade ago by Jane Driver and Lloyd Demetrius, based on mathematical arguments.
Unraveling the inverse relationship between cancer and neurodegenerative diseases may ultimately help treat or prevent these common conditions. But many questions remain unanswered. “Both cancer and dementia are actually a bunch of different diseases,” says Erin Abner. “We don’t have the granularity of data to make strong conclusions about any type of disease.” In addition, there is a long latency period between the development of pathology and the onset of symptoms, both in cancer and Alzheimer’s, which raises questions about the timing of this inverse relationship.
These enigmatic findings have no practical relevance for now. “But even now it might just be a piece of comfort for cancer survivors, that something is going to be a little easier for them down the road,” says Abner.
