Summary: New multicenter research shows that exceptional memory in advanced age—seen in “SuperAgers”—is not explained merely by having a lower inherited genetic risk for Alzheimer’s disease.
Researchers assessed 142 SuperAgers (people in their 80s and 90s whose memory scores match or exceed those typical of individuals decades younger) and 89 cognitively average peers across five research sites in the U.S. and Canada.
By examining APOE status and contemporary polygenic risk scores derived from thousands of genetic variants, the team found no genetic signature that reliably distinguishes SuperAgers from typical older adults. The results emphasize the need to uncover active protective pathways and whole-person lifestyle or environmental factors that promote cognitive resilience.
Key Facts
- Targeted cohort: The study evaluated 142 prospectively enrolled SuperAgers (aged 80 and older with episodic memory on par with people in their 50s and 60s) and 89 age-matched, cognitively average controls from five North American sites.
- APOE and polygenic risk: Analyses showed that APOE genotype distribution and three contemporary Alzheimer’s polygenic risk scores (PRS) could not distinguish SuperAgers from cognitively average peers.
- No excess of rare protective variants: Previously reported rare genetic variants linked to resilience against Alzheimer’s disease were not more common in the SuperAger group.
- Implication for aging research: The absence of common genetic risk factors does not equate to the presence of protective biology; exceptional cognitive aging appears to involve mechanisms distinct from just reduced disease risk.
- Future directions: The SuperAging Research Initiative will expand to integrate blood biomarkers, advanced neuroimaging, neuropathology, immune profiling, sleep and activity monitoring, and social and environmental measures to identify active protective pathways.
Source: University of Chicago
Overview: Many assume some memory decline is unavoidable with age. Yet a distinct group of older adults—called SuperAgers—maintain memory performance into their 80s and 90s that rivals people decades younger. Two decades of research has documented biological, neural, and psychosocial features of SuperAgers, but a central question remained: do SuperAgers simply inherit unusually low genetic risk for Alzheimer’s disease?
If genetic protection alone explained SuperAging, then identification could be simplified to genetic testing rather than the comprehensive cognitive evaluations currently used. To test this idea, investigators used the largest prospectively enrolled SuperAger cohorts available together with up-to-date Alzheimer’s genetic risk measures.
Published in Alzheimer’s Research & Therapy, the study shows that exceptional memory in advanced age cannot be reduced to low inherited Alzheimer’s disease risk, reinforcing the need to study protective biology and life-course factors directly.
A team led by the Healthy Aging & Alzheimer’s Research Care (HAARC) Center at the University of Chicago and the Translational Genomics Research Institute (TGen) assessed a diverse sample from five sites in the U.S. and Canada: 142 SuperAgers and 89 cognitively average controls. DNA derived from blood samples was used to evaluate APOE genotypes and to compute three polygenic risk scores based on recent large genome-wide association studies (GWAS).
The central result was clear: SuperAgers could not be separated from cognitively average older adults by APOE genotype or by any of the polygenic risk scores examined. In short, having exceptional memory at age 80+ is not simply explained by having exceptionally low inherited Alzheimer’s genetic risk.
“Preserving cognitive health involves more than lowering Alzheimer’s disease risk,” said Ana Capuano, PhD, co-first author and director of the biostatistics core at HAARC. “Identifying the biological, behavioral, and social drivers of exceptional cognitive aging will complement disease-focused approaches and inform more personalized strategies to support brain health.”
Even rare genetic variants previously proposed to confer resilience did not show increased prevalence among SuperAgers in this cohort, further supporting the conclusion that commonly measured genetic risk and known rare protective variants do not explain the SuperAging phenotype.
“This study establishes an important boundary for Alzheimer’s genetics,” said Matt Huentelman, PhD, co-senior author. “APOE and current AD polygenic scores do not account for SuperAging. The field should move beyond disease-risk frameworks to investigate broader biological, environmental, and experiential contributors to exceptional cognitive aging.”
Future work will use a multidisciplinary approach combining sensitive cognitive testing with neuroimaging, blood biomarkers, detailed genetics, neuropathology, immune measures, sleep and activity monitoring, and social-environmental metrics—an integrated strategy aimed at discovering mechanisms of active protection and resilience.
“For years, aging research emphasized risk factors for disease,” said Ignazio S. Piras, PhD, co-first author. “This study highlights that the mere absence of risk does not equal the presence of protective factors. Identifying those positive drivers is essential to promoting cognitive health for more people.”
The findings offer a hopeful takeaway: memory decline is not inevitable. Some individuals preserve remarkably youthful memory well into their 80s and beyond. SuperAger participants have been essential partners in this research, generously contributing time and data that point toward new routes for building resilience across the lifespan.
Funding: Supported by the National Institute on Aging (U19AG073153), the McKnight Brain Research Foundation through the SuperAging Research Initiative, the Simons Foundation, and contributions from participants, families, and collaborating investigators at five research sites.
Key Questions Answered:
A: SuperAgers are adults aged 80 or older who complete rigorous cognitive testing and demonstrate episodic memory performance equal to or better than cognitively normal individuals in their 50s and 60s.
A: No. This study found that SuperAgers share similar APOE profiles and polygenic risk scores with cognitively average older adults, so current genetic risk testing does not predict SuperAging status.
A: Researchers are expanding beyond disease-risk models to study active protective pathways, combining cognitive tracking with brain imaging, blood biomarkers, immune profiling, neuropathology, sleep and activity measures, and social-environmental factors.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by staff.
- Additional context was added by editorial staff to clarify implications for aging research.
About this genetics and aging cognition research news
Author: Grace Niewijk
Source: University of Chicago
Contact: Grace Niewijk, University of Chicago
Image credit: Neuroscience News
Original Research: Open access. Title: “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. 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 populations age, advancing age remains the strongest predictor of cognitive decline, creating a pressing need to identify biological mechanisms that support exceptional cognitive aging. This study tested whether lower inherited Alzheimer’s disease risk predicts SuperAger status (adults aged 80 and older with episodic memory at least as good as middle-aged adults) using a prospectively enrolled multisite cohort.
Methods
The analysis included 231 participants (142 SuperAgers and 89 cognitively average controls). Genetic ancestry structure was confirmed to be comparable across groups. Researchers evaluated APOE status (ε2, ε3, ε4) and three Alzheimer’s polygenic risk scores derived from contemporary GWAS (PRS_Lambert, PRS_Wightman, PRS_Bellenguez) using logistic regression models adjusted for age, sex, and education, and examined ancestry interactions.
Results
APOE allele and genotype distributions were similar between groups. Neither APOE nor any of the three polygenic risk scores predicted SuperAger status. Findings were consistent when accounting for non-European ancestry or principal components. In this well-characterized cohort, common-variant AD genetic risk measures did not explain SuperAger status.
Conclusions
These results indicate that the exceptional late-life memory seen in SuperAgers is not explained by common-variant AD genetic risk captured by APOE or current polygenic risk scores, motivating deeper investigation into rare genetic variations and non-genetic experiential factors that may support exceptional cognitive aging.