Bengaluru: Exceptional memory in old age isn’t simply a matter of winning the genetic lottery.
For nearly two decades, scientists have been studying a rare group of older adults known as “SuperAgers”—people in their 80s and 90s whose memory performs as well as, or even better than, that of people decades younger. One of the most enduring theories was that these individuals had simply inherited fewer genes associated with Alzheimer’s disease.
A new study suggests that explanation may be too simple.
Researchers from the University of Chicago and the Translational Genomics Research Institute (TGen), part of City of Hope, found that SuperAgers carry much the same inherited genetic risk for Alzheimer’s disease as other cognitively average older adults. The findings, published in Alzheimer’s Research & Therapy this month, suggest that exceptional cognitive ageing cannot be explained merely by an absence of Alzheimer’s risk genes.
Instead, scientists say, the answer is likely to lie in a complex interplay of biological, behavioural, social and environmental factors that help protect the ageing brain.
The term “SuperAger” was coined in 2008 by neuroscientist Emily Rogalski, now director of the Healthy Aging & Alzheimer’s Research Care (HAARC) Center at the University of Chicago. Since then, researchers have identified several unusual traits among these individuals—from slower brain shrinkage and larger neurons in memory-related regions to stronger social connections and psychological resilience. But one question remained unresolved: were SuperAgers simply people who had escaped Alzheimer’s genetically?
“If that were true, identifying SuperAgers might be as simple as performing genetic testing rather than the comprehensive cognitive evaluations we currently use,” Rogalski said in a statement.
To test the idea, researchers analysed blood samples from 142 SuperAgers and 89 cognitively average older adults recruited across five research sites in the United States and Canada. They examined variants of the APOE gene—the strongest known genetic risk factor for Alzheimer’s disease—and calculated three polygenic risk scores, which combine the effects of thousands of genetic variants associated with inherited Alzheimer’s risk.
SuperAgers could not be distinguished from their peers based on either APOE status or polygenic risk scores. Nor were they more likely to carry rare genetic variants previously linked to resistance against Alzheimer’s disease.
Changing the subject of study
Much of Alzheimer’s research has focused on identifying factors that increase the risk of dementia. But avoiding disease and maintaining exceptional cognitive function may not be the same biological process.
“The absence of risk factors does not necessarily mean someone possesses the protective factors that support exceptional brain health,” said Ignazio Piras, associate professor at TGen and one of the study’s co-first authors.
The study also highlights the limits of current genetic tools.
While genes such as APOE remain among the strongest predictors of Alzheimer’s disease, they do not appear sufficient to explain why some people retain remarkably youthful memory well into their 90s. According to co-senior author Matt Huentelman, common genetic risk factors explain Alzheimer’s susceptibility but not the broader phenomenon of exceptional cognitive ageing.
Researchers caution that the findings do not diminish the importance of genetics in Alzheimer’s disease, nor do they suggest that lifestyle alone determines who becomes a SuperAger. Rather, they indicate that scientists may need to look beyond disease-risk models to understand what actively protects the ageing brain.
The next phase of research will combine genetics with brain imaging, blood biomarkers, immune profiling, neuropathology, sleep and activity monitoring, and social and environmental measures to identify those protective mechanisms.
As populations age worldwide and dementia cases continue to rise, researchers say understanding why a small group of people preserve exceptional memory may prove as valuable as understanding why others lose it.
Rather than asking what causes Alzheimer’s disease, the challenge is to understand what enables some brains to remain resilient despite advancing age.