SuperAgers defy genetic risk scores in new longevity study
Research showing 80- and 90-year-olds with exceptional memory share the same Alzheimer’s genetic risk as average peers casts doubt on the precision medicine industry's reliance on DNA testing.
A study published in Alzheimer’s Research & Therapy found that people in their 80s and 90s with the memory of someone decades younger carry the same genetic risk for Alzheimer’s disease as cognitively average adults. Researchers from the University of Chicago’s HAARC Center and TGen, part of City of Hope, analyzed DNA from 142 "SuperAgers" and 89 cognitively average peers across five sites in the US and Canada.
The team examined APOE, the gene most strongly linked to Alzheimer’s, alongside broader polygenic risk scores that combine thousands of genetic variations. They found no meaningful differences between the two groups, nor did they find disparities in rare genetic variants previously linked with disease resilience.
For the precision medicine and longevity investment sectors, the findings challenge a core premise. Companies developing commercial genetic risk profiles have marketed polygenic risk scores as predictive tools for healthy aging. This data suggests such tests cannot identify exceptional cognitive resilience. “Common genetic risk factors captured by APOE and current polygenic risk scores do not explain the SuperAging phenotype,” said Matt Huentelman, PhD, a professor at TGen.
The longevity market may therefore need to shift its focus from DNA sequencing toward understanding active biological protection. “If that were true, identifying SuperAgers might be as simple as performing genetic testing rather than the comprehensive cognitive evaluations we currently use,” said Emily Rogalski, PhD, who established the SuperAging definition in 2008. Since genetics alone failed to explain the phenomenon, the field must now look elsewhere.
Future research will likely combine brain imaging, blood biomarkers, and immune profiling with data on sleep, physical activity, and social engagement. “For many years, aging research has focused on identifying factors that increase the risk of disease,” said Ignazio S Piras, PhD, an associate professor at TGen. “Those studies are critically important, but the absence of risk factors does not necessarily mean someone possesses the protective factors that support exceptional brain health.”
Pinpointing these hidden shielding factors could ultimately shape a new generation of preventative therapeutics and lifestyle interventions. “Understanding the biological, behavioral, and social factors that promote exceptional cognitive aging may ultimately complement traditional disease-focused approaches and help inform more personalized strategies for supporting brain health across the lifespan,” said Ana Capuano, PhD. The longevity industry’s next breakthrough will depend on looking beyond genetic risk to understand how ordinary genes produce extraordinary brains.
