Many people assume that some memory decline is an inevitable consequence of getting older. But a select group of older adults, known as SuperAgers, reach their 80s and 90s while retaining memory performance as good as or better than people in their 50s and 60s.

Nearly two decades of research has identified unique biological, brain, and psychosocial characteristics associated with SuperAgers, but an important question has remained: Could SuperAgers simply be people who inherited very little genetic risk for Alzheimer's disease?

"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, director of the Healthy Aging \& Alzheimer's Research Care (HAARC) Center at the University of Chicago, who established the definition of SuperAging in 2008 and has been studying this remarkable population ever since.

A new study aimed to directly test that hypothesis using the largest prospectively enrolled SuperAging cohorts and the most up-to-date Alzheimer's genetic risk measures available. The findings, published in Alzheimer's Research \& Therapy, show that exceptional memory aging cannot be explained simply by low inherited Alzheimer's disease risk, reinforcing the importance of studying protective pathways directly.

A team led by researchers at the HAARC Center and the Translational Genomics Research Institute (TGen), part of City of Hope, studied a diverse cohort from across five regional sites in the U.S. and Canada comprised of 142 SuperAgers and 89 cognitively average peers. Using DNA extracted from blood samples, the researchers examined the APOE gene, the strongest genetic risk factor for Alzheimer's disease, and calculated three polygenic risk scores, which tally thousands of genetic variants associated with inherited Alzheimer's disease risk.

The results provided a clear answer to the central question: SuperAgers could not be distinguished from cognitively average older adults based on either APOE or Alzheimer's polygenic risk scores. In other words, having exceptional memory in one's 80s is not simply explained by having exceptionally low inherited Alzheimer's disease risk.

"The findings reinforce that preserving cognitive health involves more than reducing Alzheimer's disease risk alone," said co-first author Ana Capuano, PhD, director of the biostatistics core at the HAARC Center. "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."

Even when examining rare genetic protective variants previously associated with resilience against Alzheimer's disease, the researchers found no increased prevalence among SuperAgers.

"This study establishes an important boundary for Alzheimer's disease genetics," said Matt Huentelman, PhD, professor and director in TGen's Early Detection and Prevention Division and co-senior author with Rogalski. "Common genetic risk factors captured by APOE and current polygenic risk scores do not explain the SuperAging phenotype. Future work should move beyond disease-risk models and investigate the broader biological, environmental, and experiential pathways that contribute to exceptional cognitive aging."

This future work will entail a multidisciplinary approach that combines detailed cognitive assessments with brain imaging, blood biomarkers, genetics, neuropathology, immune profiling, sleep and activity monitoring, social and environmental measures, and other indicators of whole-person health.

"For many years, aging research has focused on identifying factors that increase the risk of disease," added co-first author Ignazio S. Piras, PhD, associate professor in TGen's Early Detection and Prevention Division. "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. This study helps demonstrate that distinction."

Ultimately, the results reinforce a hopeful message: memory decline is not inevitable, and some people can - and do - maintain remarkably youthful memory well into their 80s and beyond. The search for how and why continues with the help of SuperAger research participants: extraordinary partners in discovery who have generously contributed their time over many years to help scientists understand what successful cognitive aging looks like and pointing toward new pathways to resilience.

To learn more about SuperAging research, visit https://superagingresearch.com/

This work was supported by the National Institute on Aging (U19AG073153), the McKnight Brain Research Foundation through the SuperAging Research Initiative, and the Simons Foundation, along with the many participants, families, and collaborating investigators across five research sites.

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