Cancer vs. Alzheimer’s Disease - A Complicated Relationship

by Women's Brain Health Initiative:There is a curious, and for many people surprising, relationship between cancer and neurodegenerative diseases such as Alzheimer’s disease. While the exact nature of the association between the two is still unknown, the findings thus far are fascinating and are pointing researchers in innovative directions as they seek treatments and cures for dementia and other brain-aging disorders.An Inverse Link Between Cancer & Alzheimer’s DiseaseGiven that cancer and Alzheimer’s disease both affect the elderly in great numbers, one may expect that there would be significant overlap between the two conditions (i.e. that many older individuals would be affected by both diseases). However, much research has discovered lower rates of cancer in dementia patients, particularly among those with Alzheimer’s disease (compared with cognitively-intact individuals), as well as lower rates of Alzheimer’s disease among cancer survivors (compared with individuals without cancer). Here are some examples of studies that have found an inverse association between cancer and Alzheimer’s disease.

• A study of 1,278 participants conducted by Driver et al. as part of the Framingham Heart Study in the U.S. revealed that cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and individuals with Alzheimer’s disease were found to have a lower risk of cancer. The risk of Alzheimer’s disease was lowest among survivors of smoking-related cancers. These results were published in the March 2012 issue of the British Medical Journal.
• Research in Northern Italy involving more than one million residents— conducted by Musicco et al. and published in Neurology in July 2013—found that the risk of cancer in patients with Alzheimer’s disease was halved, and the risk of Alzheimer’s disease in patients with cancer was 35% lower.
• A 2014 article by Ma et al., published in the Journal of Alzheimer’s Disease, reviewed research conducted between 1966 and 2013 and found six studies to include in their meta-analysis (a statistical procedure for combining data from multiple research studies). They, too, found an inverse association between cancer and Alzheimer’s disease. Their results showed that individuals with Alzheimer’s disease have a 42% less chance of subsequent cancer, while those with a history of cancer had a 37% less chance of developing Alzheimer’s disease.

Other researchers, however, have come to different conclusions. One study conducted by Frain et al., presented at the 2013 Alzheimer’s Association International Conference, found an inverse link between Alzheimer’s disease and some kinds of cancers, but not others. Using data on nearly 3.5 million individuals who were part of the U.S. National Veterans Health System Cohort, the researchers investigated the relationship between Alzheimer’s disease and 19 types of cancer.They discovered that most types of cancer, including pancreatic, lung, and liver, were associated with decreased risk of Alzheimer’s disease (the degree of reduced risk varied from 10% to 51%). Exceptions to this pattern were found for cancers that are commonly screened for, such as prostate cancer and melanoma. These types of cancer were associated with increased risk of Alzheimer’s disease (14% for melanoma and 11% for prostate cancer). Other types of cancer were found to have no significant association with Alzheimer’s disease, including colorectal, stomach, bladder, genital, thyroid, sarcoma, and brain. When the researchers analyzed all 19 cancers combined, the overall result was a 3% increase in the risk of Alzheimer’s disease. This number was largely driven by prostate cancer, the most common cancer in the veteran cohort.However, perhaps there is no true relationship between cancer and Alzheimer’s disease at all. Freedman et al. reported in the 2016 issue of Cancer Medicine that their findings do not support a relationship between cancer and Alzheimer’s disease. These researchers examined whether the cancer-Alzheimer’s disease association found in previous epidemiologic studies may be the result of “ascertainment bias” (as opposed to biological mechanisms), which occurs when the results or conclusions of a trial are systematically distorted due to the way in which the data is collected.The researchers hypothesized that an alternative explanation of the inverse association finding is that Alzheimer’s disease is less likely to be diagnosed in individuals with cancer and vice versa. To explore this possibility, Freedman and his colleagues analyzed data from a large group of U.S. Medicare patients and used an innovative “negative control” group (one in which no response/effect is expected): individuals with injuries from automobile accidents.Like many previous studies, the researchers discovered reduced risk of cancer among patients with Alzheimer’s patients (specifically, a 14% lower risk). However, that risk reduction was comparable to the cancer risk reduction they found after automobile accident injuries.The researchers did not expect that there would be an association between cancer and automobile accident injuries since there is no known biological relationship between the two. Yet, they did find an association, which supports the idea that ascertainment bias is at least part of the reason why researchers are finding an inverse link between cancer and Alzheimer’s disease. It appears that cancer is less likely to be diagnosed in patients with Alzheimer’s disease or other serious medical conditions. In other words, it is possible that cancer is, in fact, present among these individuals but is simply not being diagnosed.There are many reasons why cancer may be under-diagnosed among Alzheimer’s patients, including the tendency for individuals with severe cognitive impairment to under-report symptoms and the fact that such individuals are less likely to participate in common screening tests for cancer. Additionally, sometimes individuals with suspected cases of cancer are not referred for diagnostic testing by their doctors and therefore are not included in cancer statistics. For instance, a survey of elderly care physicians in the Netherlands explored non-referral of suspected breast cancer cases and discovered that end-stage dementia was cited as a reason for non-referral by 57% of the participants. (This study, conducted by Hamaker et al., was published in the Journal of the American Medical Directors Association in 2012.)When it comes to assessing the risk of cancer patients subsequently developing Alzheimer’s disease, “selective mortality” can be a factor that further complicates matters. It is possible that cancer survivors appear to have a lower risk of Alzheimer’s disease simply because these individuals are more likely to pass away before Alzheimer’s disease develops.Potential Implications for Dementia TreatmentClearly there is no consensus at this point about the link, if any, between cancer and Alzheimer’s disease. Nevertheless, studying the potential association between cancer and dementia is intriguing for researchers, in part, because a deeper understanding of the relationship between the two may assist in the development of new treatments for dementia. Indeed, some researchers have been exploring the possibility of repurposing cancer drugs to treat dementia.Several studies are testing anti-cancer drugs on mice and examining the effects on their brains and cognitive functioning. For example, epothilone D (EpoD), a drug used in the treatment of cancer, showed promise as a potential treatment for Alzheimer’s disease in a study conducted by Zhang et al. from the University of Pennsylvania. The study involved “PS19” mice that were genetically modified to experience Alzheimer’s-like changes later in life (e.g. developing widespread tau tangles and experiencing age-associated cognitive impairment).Aged PS19 mice that received low doses of EpoD for three months experienced positive physical changes in their brains, as well as improved cognitive performance, with no negative side effects. The researchers concluded that EpoD could be a candidate for clinical testing (i.e. trials to determine whether it is safe and effective for humans). These findings were shared in the March 2012 issue of The Journal of Neuroscience.Another example is the anti-cancer drug, dibenzoylmethane, which was found to restore memory and reduce brain shrinkage in mice with a type of genetic dementia during a study conducted by Halliday et al. The drug also restored protein production in the brains of the mice, an indication that neurodegeneration was being halted. The researchers concluded in their paper—published in Brain: A Journal of Neurology in June 2017—that this compound could represent a potential new disease-modifying treatment for dementia.It is necessary to keep in mind, though, that while animal experiments offer hints of possible treatments, they often fail to accurately predict what will happen in human trials. Promising results in animal studies do not necessarily translate into successful treatment outcomes in studies of humans.Importantly, some human trials are also underway that are examining the effectiveness of repurposed cancer drugs for treating dementia. For example, leuprolide acetate (Lupron Depot)—a drug used to treat advanced prostate cancer and severe endometriosis—was given to women with mild to moderate Alzheimer’s disease as part of a 48-week study by Bowen et al., the results of which were reported in the January 2015 issue of the Journal of Alzheimer’s Disease.The researchers found that cognitive function was preserved in women treated with a high dose of Lupron Depot, provided that they were already using an acetylcholinesterase inhibitor (such as Aricept, which can improve mood in people with Alzheimer’s disease but does little to slow memory loss). These women had almost no decline in scores on the Alzheimer’s Disease Assessment Scale—Cognitive (ADAS-cog), which is used to test memory. The researchers indicated that this combination therapy (acetylcholinesterase inhibitors and Lupron Depot) appears promising and warrants testing in early and late stages of Alzheimer’s disease.Potential Cognitive Consequences of Cancer TreatmentResearch from the early 2000s suggested that up to 75% of individuals treated for cancer experience cognitive impairment afterwards—a condition sometimes referred to as “chemo brain” or “chemo fog,” even though chemotherapy itself may not be the cause (stress and depression may also affect cancer patients’ performance on cognitive tests, for instance). This phenomenon of “chemo brain” led researchers to wonder whether cancer treatments may increase the risk of developing dementia.An academic review, published in the 2013 edition of Aging Health, noted that the issue of whether cancer treatment is leading to dementia “has been studied and the results in published literature have been mixed.” Despite the inconsistent results, the researchers suggested that there is increasing evidence that most types of treatment for cancer do have a negative impact on cognition.Other research presented that same year at the Alzheimer’s Association International Conference (conducted by Frain et al. from Boston, Massachusetts) found that among patients treated for cancer, chemotherapy treatment further reduced the risk of Alzheimer’s disease.Much More to LearnConsistent with virtually all aspects of dementia, there is much left to learn—in this case, about the relationship between cancer and dementia. Given the vast numbers of individuals facing these two deadly diseases, the need for this research is imperative.Source: MIND OVER MATTER - V5