Summary: A new study reveals that exceptional memory in older adults is not driven simply by low inherited Alzheimer’s disease risk.
The multi-center study evaluated 142 SuperAgers (adults in their 80s and 90s with memory performance matching individuals decades younger) alongside 89 cognitively average peers across five sites in the U.S. and Canada.
The team analyzed APOE variants and comprehensive polygenic risk scores. The findings demonstrate that SuperAgers cannot be differentiated from average peers based on genetic disease risk, emphasizing the urgent need to identify active protective pathways and holistic lifestyle factors driving cognitive resilience.
Key Facts
- Target Cohort Design: The study analyzed 142 prospectively enrolled SuperAgers (aged 80 and older with memory capability equal to or exceeding individuals in their 50s and 60s) and 89 age-matched, cognitively average controls across five North American research sites.
- APOE and Polygenic Risk Parity: Genotypic analysis showed that neither $APOE$ allele status nor three distinct Alzheimer’s polygenic risk scores (PRS) incorporating thousands of risk variants could distinguish SuperAgers from cognitively average peers.
- Rare Variant Absences: The study also evaluated rare genetic protective variants previously associated with resilience against Alzheimer’s disease and found no increased prevalence among the SuperAger cohort.
- Paradigm Shift in Aging Research: The findings establish that the absence of standard genetic risk factors is insufficient to produce exceptional cognitive aging, separating the biology of disease risk reduction from active brain protection.
- Future Multidisciplinary Directions: Future SuperAging Research Initiative protocols will integrate blood biomarkers, advanced neuroimaging, neuropathology, immune profiling, sleep tracking, and social-environmental metrics.
Source: University of Chicago
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/
Funding: 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.
Key Questions Answered:
A: SuperAgers are individuals in their 80s, 90s, or beyond who undergo rigorous cognitive testing and demonstrate memory capacity equal to or better than cognitively normal individuals in their 50s and 60s.
A: No. This study proves that SuperAgers share similar $APOE$ profiles and polygenic risk scores as cognitively average older adults, meaning genetic testing for Alzheimer’s risk cannot predict or identify SuperAging capabilities.
A: Researchers are moving beyond disease-risk models to study active protective pathways, combining detailed cognitive tracking with brain imaging, blood biomarkers, immune profiling, neuropathology, sleep architecture, and social-environmental factors.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and aging cognition research news
Author: Grace Niewijk
Source: University of Chicago
Contact: Grace Niewijk – University of Chicago
Image: The image is credited to Neuroscience News
Original Research: Open access.
“SuperAging is not the inverse of common variant Alzheimer’s risk: evidence across genetic ancestries” by Ignazio Stefano Piras, Ana Werneck Capuano, Amanda Cook Maher, Rhiana Schafer, Anna Bonfitto, Serena Song, Francis Taguinod, Felicia Goldstein, Angela Roberts, Ozioma Okonkwo, Adam Martersteck, The SuperAging Research Initiative, Matt J. Huentelman & Emily Rogalski. Alzheimer s Research & Therapy
DOI:10.1186/s13195-026-02124-2
Abstract
SuperAging is not the inverse of common variant Alzheimer’s risk: evidence across genetic ancestries
Background
As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer’s disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative.
Methods
We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRSLambert, PRSWightman, PRSBellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions.
Results
APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status.
Conclusions
These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.
