Cancer wastes you physically, and Alzheimer’s mainly thins out your cognitive ability. Two different diseases, two different patterns, yet they influence each other. Rarely do researchers find the same person having cancer and Alzheimer’s, fuelling the speculation that one of the conditions might shield a person from the other.
The answer to this medical riddle took 15 years to uncover, as a paper published in Cell describes how a protein produced by cancer cells appears to infiltrate the brain. Alzheimer’s is caused by plaques of beta-amyloid protein that clump in the brain, jeopardizing neural connections and leading to cognitive impairment. The proteins released by cancerous cells come in clutch by breaking apart these plaques, which are heavily associated with Alzheimer’s. The research can help scientists design better drugs for Alzheimer’s.
Epidemiological data blurs the border between cancer and Alzheimer’s; however, a meta-analysis of data in 2020 from 9.6 million people diagnosed with cancer had 11% decreased incidence of Alzheimer’s disease. The relation has been tough to set a standard for, as a large number of external factors need to be controlled to remove ambiguity. For instance, people might die from cancer before showing symptoms of Alzheimer’s, which mostly start in older ages. Cancer medications are also known to cause cognitive difficulties, which can obscure an Alzheimer’s diagnosis.
However, the data collected over the years were sufficient to convince Youming Lu, a neurologist at Huazhong University of Science and Technology in Wuhan, China, to investigate the biological underpinnings of this trend. Researchers in Lu’s laboratory spent years finding the best way to model both the conditions in mice. The team settled on transplanting three different types of human tumor— lung, prostate, and colon— into mouse models of Alzheimer’s. The amyloid plaques characteristic of Alzheimer’s were absent in the mice with cancer.
Out of hundreds of proteins released by cancer cells, the researchers focused on the ones that can infiltrate the brain by crossing the protective boundary known as the blood-brain barrier. Blood carries multiple substances into the brain, and the blood-brain barrier serves as the gatekeeper, allowing some to enter while preventing others from entering. The researchers spent about 6 years narrowing the list to one protein: cystatin C.
Cystatin C binds to the molecular hallmark of the brain plaques in Alzheimer’s disease. This interaction activates TREM2, a signalling protein, found on specific immune cells that patrol the brain. These immune cells continue to degrade the plaques, and in Lu’s mice, this degradation improved the mice’s performance on cognitive tests.
However, bypassing the blood-brain barrier for cystatin C is like stuffing a Goliath through a trapdoor. Lu explains that research has found that the blood–brain barrier weakens in people with early Alzheimer’s disease. This should allow cystatin C to pass through, but whether it weakens enough to allow cystatin C to enter the brain before symptoms of Alzheimer’s disease are noticed is unclear.
Researchers have been trying to find drugs that can activate TREM2 to counter Alzheimer’s, but have struggled as most drugs disable proteins. Cystatin C is one of the rare proteins that trigger a signalling cascade to eliminate plaques. TREM2 activators have yielded mixed results in clinical trials so far, but Alzheimer’s cannot be cured with just one drug. Instead, a cocktail of drugs will be required. The next chapter in this research is to find a way to replicate the results in humans, setting up a whole new arsenal of therapy for Alzheimer’s.
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