Columbia researchers have identified a way to help predict when people at high risk of developing Alzheimer’s disease are likely to develop their first symptoms, a finding that could help physicians determine when to begin preventive interventions currently under development. The approach combines a blood biomarker with genetic testing to estimate how close an individual may be to symptom onset.
The research team, led by Richard Mayeux, M.D., MSc, neurologist-in-chief at NewYork-Presbyterian and Columbia and chair of the Department of Neurology at Columbia, analyzed data from roughly 8,500 older adults across diverse racial and ethnic backgrounds and found that combining two Alzheimer’s tests — a blood test that measures plasma tau phosphorylated at threonine 217 (p-tau217), a known biomarker of neuropathological changes associated with Alzheimer’s, and a genetic test that identifies a high-risk variant of the apolipoprotein E (APOE) gene — can predict symptom onset in people who are not currently cognitively impaired. Their findings were recently published in The Lancet Neurology.
“The combination of the tests really makes a difference in predictive power. And the projections are the same for everyone regardless of their background,” says Dr. Mayeux. “What this will allow us to do is make better predictions about the onset of symptoms in people at risk, and when preventative drugs become available, prescribe those at the right time.”
Illustration of the APOE4 gene. By combining testing for elevated p-tau217 levels with genetic testing for APOE4, Columbia researchers were able to predict when patients at high risk for Alzheimer’s disease might develop symptoms.
How p-tau217 and APOE4 Testing Improves Alzheimer's Risk Prediction
Among participants with elevated p-tau217 tau levels, those carrying one or more copies of the high-risk APOE4 gene were likely to develop symptoms within three to four years, compared with five to six years for those with other APOE variants.
In the last few years, new blood tests that measure ptau-217 have changed the landscape of Alzheimer’s diagnosis, and neurologists now commonly use the test to confirm or rule out Alzheimer’s disease in older adults with memory loss or cognitive decline. Elevated p-tau217 levels can also be detected in people who have not yet developed symptoms, raising the possibility of using ptau as an early indicator of Alzheimer’s.
However, p-tau217 alone does not provide sufficiently precise estimates of when cognitive impairment is likely to occur, which is why investigators chose to study its combination with APOE4, the strongest known genetic risk factor for Alzheimer’s disease — about one in five people have at least one copy of the gene.
The combination of the tests really makes a difference in predictive power. What this will allow us to do is make better predictions about the onset of symptoms in people at risk, and when preventative drugs become available, prescribe those at the right time.
— Dr. Richard Mayeux
Implications for Prevention and Future Treatment
Despite the study’s promising findings, Dr. Mayeux doesn’t currently recommend patients undergo the testing because only symptomatic patients are eligible to receive monoclonal antibody therapies that are approved for Alzheimer’s — but that could change quickly as prevention-focused studies move forward.
Ongoing research at Columbia is evaluating whether the antibody drugs can slow disease progression when administered to asymptomatic people with elevated p-tau217 levels. Additional therapies aimed at preventing or delaying the disease and its symptoms are also currently in development.
Ultimately, the Columbia findings move the field closer to a longstanding goal in Alzheimer's research: identifying and treating at-risk individuals before symptoms appear. For future prevention-focused clinical trials, the investigators’ findings may help identify when interventions are most likely to have the greatest impact.
“If you have a drug that could prevent disease, what would be the optimal time to give it to people?” says Dr. Mayeux. “Our data is telling us, for people at high risk with APOE4 genes, the best time is when their p-tau levels elevate, about three years before symptoms emerge.”
A version of this article originally ran on the Columbia newsroom.
