In recent years, scientists around the world have been probing an unexpected trend: The risk of developing cancer seems to have an inverse relationship with the risk of developing Alzheimer’s disease.

Research published earlier this year in Brain, in which researchers autopsied study subjects to verify whether they had in fact died with Alzheimer’s disease, further solidifies the hypothesis, experts tell The Scientist.

Thanks to those data, which showed participants with cancer had fewer hallmarks of Alzheimer’s disease in their brains as well as a reduced likelihood of neurodegenerative symptoms during their lifetimes, lead study author Erin Abner, a University of Kentucky epidemiologist and aging researcher and her team were able to offer the clearest picture yet of a molecular mechanism that seems to link the two diseases.

“The connection is becoming more and more apparent,” New York University cancer researcher Eva Hernando-Monge, who didn’t work on the study, tells The Scientist.

A neurological link between cancer and Alzheimer’s

Nearly every prior study exploring the connection between cancer and Alzheimer’s in humans did so by analyzing epidemiological evidence. For example, a 2020 meta-analysis and literature review published in JAMA Network Open combined 22 cohort studies representing more than 9.6 million people to calculate that cancer diagnoses are associated with an 11 percent reduction in Alzheimer’s disease occurrence.

The Brain study expands on that approach. In it, researchers monitored volunteers through the University of Kentucky’s Alzheimer’s Disease Research Center, which follows people throughout their lives—often for decades—and allows their symptoms and pathologies to be directly connected to biological data from their autopsies after they die, Abner tells The Scientist. 

The researchers used data including clinical diagnoses and scores on the Mini-Mental State Exam, a popular tool used to diagnose dementia and track its progression. Those data were compared to cohort members’ records from the University of Kentucky’s cancer registry, which is legally required to include every cancer diagnosis and treatment in the state. Participants were included in the analysis regardless of the stage or treatment status of their cancer, though the researchers repeated the analysis among just those who were cancer-free at baseline.

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As cohort members passed away, the team autopsied their brains to look for biomarkers associated with Alzheimer’s disease, including structures such as neurofibrillary tangles and neuritic plaques. They also noted when someone carried the APOE ε4 allele, a known genetic risk factor for the neurodegenerative condition. This allowed for a more accurate diagnosis than studies without access to autopsies or with less access to the patients. In order to avoid confounding factors, the team only included data from subjects who didn’t show signs of dementia at their baseline examination, explaining in their paper that such a diagnosis might prompt behavioral changes that could potentially complicate the analysis. While this reduced the number of participants to 785, far lower than most cohort studies, experts tell The Scientist that the multifaceted methodology means that the data were of particularly high quality.

The analysis revealed “less Alzheimer’s pathology in the people who had cancer, both amyloid and tau,” Abner says. “We also saw evidence [that] another amyloid pathology—cerebral amyloid angiopathy, which is amyloid aggregation in blood vessel walls—was lower. Another contribution of our study is that we found an inverse association with APOE, a major genetic driver of Alzheimer’s risk, and cancer. Most of the existing studies on cancer and dementia have not been able to use these kinds of data.”

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Jane Driver, who studies aging and the Alzheimer’s-cancer link at the US Department of Veterans Affairs and Harvard Medical School but didn’t contribute to the Brain paper, says that the new publication fills in a gap “for which there isn’t a lot of evidence, which is a biological-level correlation between what people’s brains look like when they die, a real objective assessment of Alzheimer’s-type pathology, and a good definition of cancer from a cancer registry.”

Biologist Ovais Shafi from Sindh Medical College in Pakistan, who also was not involved in the research, similarly tells The Scientist over email that the study’s design and methodology “make the findings of the study more impactful and clear” than those of previous purely epidemiological papers on the link.

The connection is becoming more and more apparent.

—Eva Hernando-Monge, New York University

Experts say that diagnosing Alzheimer’s disease—by examining autopsied brains for specific Alzheimer’s biomarkers—is crucial for cutting noise from the data and painting a clear picture of the relationship between cancer and Alzheimer’s.

That’s because there are many kinds of dementia that can be caused by myriad factors such as strokes, Driver says, and it’s impossible to diagnose a dementia patient with perfect accuracy until after they’ve died and their brain can be autopsied. Without the ability to confirm an Alzheimer’s diagnosis, data from people with other forms of dementia can muddle the results: as Driver explains, the inverse correlation with cancer diagnosis only seems to exist for Alzheimer’s disease, not with dementia in general.

Possible mechanisms for a cancer-Alzheimer’s risk connection

Compared to the evidence that a correlation exists, scientists’ understanding of the mechanisms driving the link between Alzheimer’s and cancer is far less robust. However, there have been some attempts to explain the link at the molecular scale.

For example, Shafi scoured existing literature to write a 2016 review in BMC Neurology that suggested each disease downregulates processes in the brain that would support the other condition. Processes related to cell growth and survival, as well as the production of specific molecules including the antistress response protein vimentin and the enzyme carbonic anhydrase, are all upregulated in cancer, he finds. Alzheimer’s occurs when these processes and proteins are downregulated.

Another review, published in Molecular Psychiatry in 2021, identifies the proteins p53 and PIN1 as implicated in both cancer and Alzheimer’s. PIN1 overexpression is associated with myriad cancers, but its absence is linked to the formation of the Alzheimer’s biomarkers tracked in the Brain study. Meanwhile, p53 has a well-established anticancer role, but can also contribute to neurodegenerative disease.

While the Brain paper primarily focused on the onset of Alzheimer’s disease among cancer patients and not vice versa, the evidence in these reviews suggests that the correlation may be bidirectional and dictated at least in part by the genetic drivers of those various processes.

Picture imperfect

Still, questions remain about exactly how the diseases are connected. For example, Shafi says it’s imperative that future research “seeks out which factors greatly contribute to [Alzheimer’s] or are causative directly or indirectly,” establishing a clearer link than the correlation identified by existing studies.

In addition to experimental studies, improving our understanding of the link will require access to even better and broader human data. One challenge is that the volunteers in the Brain study were overwhelmingly white and highly-educated—with an average of 15 years of schooling—making them poorly representative of the broader population and potentially skewing the study results, explains University of Michigan School of Public Health social epidemiologist Lindsay Kobayashi, a coauthor of the JAMA Network Open meta-analysis.

“An important thing to remember about research studies that use autopsy data is that they have used data from people who have died, and these people might have different neuropathology than those who live for a long time,” Kobayashi adds. Among the participants whose data were included in the final study, the average age of death was just under 84 years old, plus or minus about nine years—a number unaffected by cancer diagnosis.

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It’s also possible that people who survive cancer and stave off Alzheimer’s happen to be healthier than the general population for some unknown reason, Driver speculates, which is to say that further studies will need to investigate and attempt to rule out other possible explanations for the phenomenon.

The burning, unanswered question is what this means for people living with dementia, cancer, or both. As far as immediate clinical applications go, the Brain paper offers little to go on. However, continuing to explore the link between cancer and Alzheimer’s could one day reveal new ways to treat or prevent both, experts tell The Scientist.

“This understanding may ultimately lead to a revolution in the development of new therapies that will be focusing on new targets in terms of molecular mechanisms and cellular pathways based on the inverse relationship between Alzheimer’s disease and Cancer,” Shafi writes.

Driver adds that there may be a biological profile of people who are more likely to develop Alzheimer’s and less likely to develop cancer—or vice versa. If scientists “can understand what’s driving those differences” and “discover what is it [that] the body’s doing to protect itself from cancer and increase the risk of Alzheimer’s,” Driver says, then there may be “something we could modulate there to come up with a new treatment.”

The melanoma exception

The Brain study identified a general trend but didn’t correlate the risk of Alzheimer’s disease with any individual type of cancer.

“Cancers are all quite different,” US Department of Veteran Affairs researcher Jane Driver tells The Scientist, with pathology that is “very different from cancer to cancer.”

Standing out from other cancers is melanoma, which has a more complicated relationship with Alzheimer’s—as well as Parkinson’s—than cancer as a whole does, New York University cancer researcher Eva Hernando-Monge tells The Scientist. Based on her work on the mechanistic connections between neurodegenerative disease pathology and melanoma metastasis, she asserts that the inverse correlation between Alzheimer’s disease and cancer risk doesn’t hold true when looking specifically at melanoma. She adds that there’s a strong positive correlation between melanoma and another neurodegenerative condition, Parkinson’s disease—a trend that’s been supported by multiple studies.

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Hernando-Monge, along with colleagues primarily from New York University, published a paper this month in Cancer Discovery in which a proteomic analysis of melanoma cells from human patients revealed that the cancer, which has one of the highest rates of brain metastasis among malignancies, can adapt to better survive the brain environment. The study, which also involved injecting human melanoma cells into mice, found that metastasizing melanoma tumors secrete amyloid beta, the peptide that builds up in the brains of people with Alzheimer’s, indicating that there’s a plausible positive connection between that cancer type and Alzheimer’s instead of the inverse relationship turned up by the Brain paper.

Those secretions, she explains, inhibit the immune system’s ability to fight melanoma cells by neutralizing astrocytes in the area. That, in turn, prevents astrocytes from summoning microglia that would target and consume the tumors—telling the astrocytes that “nothing is going on, stay there, don’t call the microglia, everything is alright,” Hernando-Monge says. That, ultimately, may prevent the brain from staving off not only melanoma but neurological conditions as well.