A toxic Alzheimer’s protein could be the key to fighting cancer

Their new study, published in Cancer Research, shows that a protein strongly associated with Alzheimer's disease can also enhance the immune system's strength. The finding could open doors to new approaches for treating cancer, neurodegenerative disorders, and age-related decline.

The Alzheimer's-cancer paradox

For years, researchers noticed something odd in population data: people diagnosed with Alzheimer's disease appeared to have a much lower risk of developing cancer. This unusual pattern intrigued Besim Ogretmen, Ph.D., associate director of Basic Science at Hollings, who set out with his team to uncover the biological explanation behind it.

Epidemiologist Kalyani Sonawane, Ph.D., led the effort to verify this correlation. Her 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 it.

Although the connection was clear, the underlying reason was not. What biological mechanism could explain why the two diseases seem to work in opposite directions?

A biological trade-off

Through a series of experiments, the researchers traced the connection to a familiar culprit: amyloid beta, the protein known for forming harmful plaques in the brains of Alzheimer's patients. They discovered that amyloid beta has a dual personality, depending on where it acts. In the brain, it damages neurons, but in the immune system, it appears to make immune cells stronger.

Amyloid beta interferes with a cellular recycling process called mitophagy, which normally removes damaged mitochondria -- the energy-producing parts of cells. In the brain, blocking this cleanup leads to a buildup of faulty mitochondria that release toxins and trigger neuron death, worsening memory loss and cognitive decline.

In contrast, when amyloid beta affects immune cells called T-cells, the outcome flips. By limiting mitophagy, it allows more mitochondria to stay functional, giving T-cells extra energy to power their cancer-fighting activity.

"What we found is that the same amyloid peptide that is harmful for neurons in Alzheimer's is actually beneficial for T-cells in the immune system," Ogretmen said. "It rejuvenates the T-cells, making them more protective against tumors."

Rejuvenating the immune system

To explore this further, the team transplanted mitochondria from T-cells of Alzheimer's patients into aging T-cells from individuals without the disease. The change was remarkable.

"Older T-cells began functioning like young, active T-cells again. That was an incredible finding because it suggests a whole new way to think about rejuvenating the immune system."

The results also revealed that amyloid beta contributes to cancer in another way -- by depleting fumarate, a small molecule made inside mitochondria during energy production. Fumarate acts like a brake, keeping mitophagy from running out of control. When fumarate levels drop, cells recycle too many of their healthy mitochondria, resulting in a loss of strength.

"When you deplete fumarate, you increase mitophagy much more," Ogretmen explained. "Fumarate no longer binds 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 to regulate this balance. When the researchers administered fumarate to aging T-cells in mice and human tissue, they found lower levels of mitophagy. By preserving their mitochondria, fumarate gave the immune cells more energy to fight cancer. The discovery that fumarate rescues aging T-cells from excessive mitochondrial loss and enhances their anti-tumor 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 might be harnessed. Rather than attacking tumors directly, this research points to a new generation of therapies that recharge the immune system itself.

One approach is mitochondrial transplantation, giving older T-cells fresh, healthy "power plants" to revitalize their disease-fighting protection. Another strategy is to maintain or restore fumarate levels to preserve mitochondria and boost T-cells' anti-tumor activity.

The potential applications for cancer are wide-ranging. Revitalizing T-cells by transplanting healthy mitochondria could strengthen existing treatments like CAR-T cell therapy. Ogretmen's group has already filed a patent for this discovery, underscoring its potential as a new class of therapy. Fumarate-based drugs or supplements might further extend the life and energy of older immune cells by preserving their mitochondria. These could be used in conjunction with immunotherapy to maintain T-cells' strength during treatment.

Beyond cancer, these approaches could help to slow immune aging more generally. As mitochondria naturally wear down over time, protecting them could help older adults to fight infections and stay healthier. Further delving into the double-edged impact of amyloid beta could also inform future treatments for neurodegenerative diseases, like Alzheimer's, by finding ways to isolate its protective immune effects without harming the brain.

For Ogretmen, the novel findings highlight the power of teamwork, noting the collaboration across Hollings' research programs in cancer biology, immunology and prevention.

"This was a true team effort," he emphasized. "We're 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."