When Margery noticed her father's confusion at the dinner table last spring, his Alzheimer's disease had already begun stealing pieces of him. What if doctors could have warned them years earlier — not just that he had the disease, but that its symptoms were coming?
That kind of early warning may be closer than we thought. A new study published in Nature Medicine found that small loops of genetic material called circular RNAs, or circRNAs, floating in the blood can predict Alzheimer's symptoms two to four years before they appear. The discovery could give families precious time to plan — and researchers a better tool to test treatments.
Scientists already have blood tests that detect amyloid plaques, the sticky buildup in the brain that marks Alzheimer's. Those tests work well and can flag the disease decades before memory problems start. But they can't tell doctors much about when — or how fast — symptoms will actually arrive.
"In a clinical setting, being able to identify patients on the verge of symptom onset would be invaluable," said Dr. Richard Hodes, director of the National Institute on Aging, which funded the research. "Having this information could help us select the right patients for clinical trials and better determine which treatments are effective at preventing cognitive decline."
The new research, led by Dr. Carlos Cruchaga and colleagues at Washington University School of Medicine in St. Louis, analyzed blood samples from more than 1,200 people across multiple studies. They identified 34 circular RNAs whose levels were strongly linked to Alzheimer's disease. Patients with elevated levels of these molecules were nearly three times more likely to develop symptoms compared to others.
When the researchers built predictive models using these 34 circRNAs, the results were striking. The model performed just as well as the current leading blood test — which measures a protein called pTau217 — at identifying people who already had Alzheimer's pathology in their brains. But when the scientists looked into the future, the circRNAs left that test in the dust. The molecules predicted symptom progression far more accurately, with their levels starting to diverge from normal about two to four years before cognitive decline became noticeable.
One reason circRNAs may be so useful is that, unlike amyloid plaques, which accumulate over decades, these tiny loops respond quickly to what's happening in the brain right now. They offer a more real-time signal.
Researchers are now working with commercial partners to turn their findings into actual clinical blood tests. "It's nice to have good science and models, but we're ultimately doing this to help people," Cruchaga said. The goal is to eventually help doctors catch Alzheimer's progression — not just the presence of plaques — giving patients and families more time to prepare.