At first, Alzheimer’s disease and cancer may seem like little overlap. One gradually destroys memory and cognition, while the other devastates the body through uncontrolled cell growth. However, scientists at MUSC Hollings Cancer Center have found an unexpected biological link between them.
His new study, published in cancer researchshows that a protein strongly associated with Alzheimer’s disease can also improve the strength of the immune system. The finding could open the door to new approaches to treating cancer, neurodegenerative disorders and age-related decline.
The paradox of Alzheimer’s and cancer
For years, researchers noticed something strange in demographic data: People diagnosed with Alzheimer’s disease seemed to have a much lower risk of developing cancer. This unusual pattern intrigued Besim Ogretmen, Ph.D., associate director of Basic Sciences at Hollings, who set out with his team to discover the biological explanation behind it.
Epidemiologist Kalyani Sonawane, Ph.D., led the effort to verify this correlation. His group examined five years of nationally representative survey data and found striking evidence: Adults over age 59 with Alzheimer’s were 21 times less likely to develop cancer than those without Alzheimer’s.
Although the connection was clear, the underlying reason was not. What biological mechanism could explain why the two diseases seem to act in opposite directions?
A biological compensation
Through a series of experiments, researchers traced the connection to a familiar culprit: amyloid beta, the protein known to form harmful plaques in the brains of Alzheimer’s patients. They discovered that amyloid beta has a split personality, depending on where it acts. In the brain, it damages neurons, but in the immune system, it appears to strengthen immune cells.
Amyloid beta interferes with a cellular recycling process called mitophagy, which normally eliminates damaged mitochondria, the energy-producing parts of cells. In the brain, blocking this cleanup leads to a buildup of defective mitochondria that release toxins and trigger neuronal death, worsening memory loss and cognitive decline.
In contrast, when amyloid beta affects immune cells called T cells, the outcome changes. By limiting mitophagy, more mitochondria are allowed to continue functioning, providing T cells with additional energy to fuel their cancer-fighting activity.
“What we found is that the same amyloid peptide that is harmful to neurons in Alzheimer’s disease is actually beneficial to the T cells of the immune system,” Ogretmen said. “It rejuvenates T cells, making them more protective against tumors.”
Rejuvenate the immune system
To explore this further, the team transplanted mitochondria from T cells from Alzheimer’s patients into aged T cells from individuals without the disease. The change was notable.
“The older T cells began to function again as young, active T cells. It was an incredible finding because it suggests a completely new way of thinking about rejuvenating the immune system.”
The results also revealed that amyloid beta contributes to cancer in another way: by depleting fumarate, a small molecule produced within mitochondria during energy production. Fumarate acts as a brake, preventing mitophagy from getting out of control. When fumarate levels drop, cells recycle too many healthy mitochondria, causing a loss of strength.
“When fumarate is depleted, mitophagy increases much more,” Ogretmen explained. “Fumarate no longer binds to the proteins involved in that process, so the proteins become more active and induce more mitophagy. It’s like a reinforcing feedback loop.”
In T cells, fumarate helps regulate this balance. When the researchers administered fumarate to aged T cells in mice and human tissue, they found lower levels of mitophagy. By preserving their mitochondria, fumarate gave immune cells more energy to fight cancer. The discovery that fumarate rescues aging T cells from excessive mitochondrial loss and enhances their antitumor activity suggests another way to protect immune health.
Broad implications for cancer and aging
Together, these findings shed light on why people with Alzheimer’s disease are less likely to develop cancer and how that protection could be harnessed. Instead of attacking tumors directly, this research points to a new generation of therapies that recharge the immune system itself.
One approach is mitochondrial transplantation, which provides older T cells with fresh, healthy “power plants” to revitalize their protection against disease. Another strategy is to maintain or restore fumarate levels to preserve mitochondria and stimulate T cell antitumor activity.
The potential applications for cancer are very broad. Revitalizing T cells by transplanting healthy mitochondria could strengthen existing treatments such as CAR-T cell therapy. The Ogretmen group has already filed a patent for this discovery, underscoring its potential as a new class of therapy. Fumarate-based medications or supplements could further prolong the life and energy of older immune cells by preserving their mitochondria. These could be used along with immunotherapy to maintain T cell strength during treatment.
Beyond cancer, these approaches could help curb immune aging more generally. Since mitochondria naturally wear out over time, protecting them could help older adults fight infections and stay healthier. Delving deeper into the double-edged impact of amyloid beta could also inform future treatments for neurodegenerative diseases, such as Alzheimer’s, by finding ways to isolate its protective immune effects without damaging the brain.
For Ogretmen, the new findings highlight the power of teamwork, highlighting collaboration between Hollings’ research programs in biology, immunology and cancer prevention.
“This was a true team effort,” he emphasized. “We are proud of the different areas of expertise that came together to make these discoveries. The research exemplifies how discoveries in one area can open unexpected doors in another.”
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