Superagers keep youthful memories but their DNA does not explain why

Scientists have spent nearly 20 years identifying the biological, neurological, and psychosocial traits linked to SuperAgers. One major question, however, has remained unresolved: Are SuperAgers simply people who inherited unusually low 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.

Testing the Genetic Explanation for SuperAging

To investigate that possibility, researchers analyzed the largest prospectively enrolled SuperAging cohorts studied with the latest measures of genetic risk for Alzheimer's disease. The results, published in Alzheimer's Research & Therapy, indicate that extraordinary memory in later life cannot be explained solely by low inherited Alzheimer's risk. The findings highlight the need to study the protective mechanisms that may help some people maintain unusually strong cognitive abilities.

Researchers from the HAARC Center and the Translational Genomics Research Institute (TGen), part of City of Hope, examined a diverse group recruited from five regional sites in the U.S. and Canada. The study included 142 SuperAgers and 89 older adults with average cognitive performance.

Using DNA obtained from blood samples, the team analyzed the APOE gene, the strongest known genetic risk factor for Alzheimer's disease. They also calculated three polygenic risk scores, which combine thousands of genetic variants associated with inherited Alzheimer's risk.

SuperAgers Show No Clear Genetic Advantage

The results directly challenged the idea that SuperAgers are protected simply because they carry fewer Alzheimer's related risk variants. Researchers could not distinguish SuperAgers from cognitively average older adults based on either APOE or the Alzheimer's polygenic risk scores.

Put simply, exceptional memory in a person's 80s does not appear to result from having exceptionally low inherited risk for Alzheimer's disease.

"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."

The researchers also examined rare genetic variants previously linked to protection or resilience against Alzheimer's disease. These variants were not more common among SuperAgers than among the comparison group.

Looking Beyond Alzheimer's Risk Genes

"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."

Future studies will use a broad, multidisciplinary strategy. Researchers plan to combine detailed cognitive testing with brain imaging, blood biomarkers, genetics, neuropathology, immune profiling, sleep and activity monitoring, social and environmental measurements, 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."

Why Some Memories Stay Young

The findings support an encouraging conclusion: memory decline is not unavoidable. Some people can -- and do -- preserve remarkably youthful memory into their 80s and beyond.

Scientists still do not know exactly how SuperAgers maintain such strong cognitive abilities, but the search continues with help from the participants themselves. These long-term research volunteers have contributed years of their time to help scientists define successful cognitive aging and identify new pathways that may promote resilience.

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.