Are Alzheimer’s disease and colorectal cancer inversely related?

Epidemiological researchers have observed that people with Alzheimer’s disease appear to develop many common cancers less often than the general population—and that people with such cancers also appear to have a lower Alzheimer’s risk. The observation has captivated scientists, but experimental evidence showing why these associations exist has been lacking. A study’s authors now say they’ve found experimental evidence to support this inverse relationship between an individual being affected by Alzheimer’s disease and colorectal cancer (Proc. Natl. Acad. Sci. 2024, DOI: 10.1073/pnas.2314337121).

Though the phenomenon has received increasing attention, “the underlying molecular mechanisms remain unclear,” Shunjiang Xu, a pathophysiologist at Hebei Medical University who led the study, wrote in an email to C&EN. “That is why we performed this study.”

Scientists first treated mice with azoxymethane and dextran sodium sulfate, which can be used to induce colorectal cancer in mice. They found that rodents exhibiting Alzheimer’s-like cognitive decline developed colorectal cancer less often than otherwise healthy mice. The researchers cited this as experimental evidence of an inverse relationship between the two diseases.

Researchers also noticed that the mice used as models for Alzheimer’s disease who were given stool transplants from healthy mice lost the apparent protective effect against colorectal cancer. This result suggested that imbalances in the gut microbiome might contribute to the phenomenon.

Further analyses showed that Alzheimer’s model mice and people with mild cognitive impairment had higher levels of bacteria belonging to the Prevotella genus than subjects in the control groups. Human patients with colorectal cancer had lower levels of Prevotella bacteria than people without cognitive impairment.

Healthy mice who were fed lipopolysaccharides from the outer membrane of Prevotella bacteria demonstrated signs of cognitive decline. When those mice received the carcinogenic treatment, they developed fewer and smaller tumors than control mice. The authors suggested that Prevotella-derived lipopolysaccharides could be responsible for both promoting cognitive decline and helping the mice build up tolerance to intestinal inflammation. That tolerance may also inhibit colorectal cancer, the researchers wrote. They emphasized that further studies are needed to confirm the findings.

“Epidemiologists have said, ‘Wow there’s this inverse correlation.’ But no concerted effort has been made to really sit down and try to understand this at a molecular level,” said Donald Weaver, a medicinal chemist and clinical neurologist at the University of Toronto who was not involved in the study.

Weaver added that the paper could provide useful information for future scientists who may want to target the microbiome for therapeutic purposes.

“The last thing we want to do is develop some anticancer techniques that, in fact, are going to stimulate dementia,” Weaver said. “A better understanding of the molecular intricacies of this inverse correlation is going to be essential for future efforts at rational therapeutics design.”