Exceptional memory in later life may depend less on inherited Alzheimer's risk and more on the biological and lifestyle factors that help some older adults stay cognitively sharp for decades.
A new study published in the journal Alzheimer's Research & Therapy
Testing whether genetics explains SuperAging
Age is the strongest predictor of cognitive decline, but the underlying mechanisms remain unclear. Cognitive decline is characterized by declining episodic memory and changes in hippocampal and cortical circuits key to memory.
Notably, SuperAgers continue to have exceptional episodic memory well into their eighties, performing at levels comparable to those of adults several decades younger, which could help clarify how memory functions are preserved in late life.
Common genetic risk for AD is most commonly assessed using APOE status and AD polygenic risk scores (PRSs), which capture the cumulative effects of thousands of common genetic variants associated with the condition.
APOE is the strongest common genetic risk factor for AD. The ε4 variant is linked to a higher risk and earlier onset of AD, whereas the ε2 variant is associated with a protective effect. Some larger studies have reported lower ε4 and higher ε2 frequency among mostly White participants with high cognitive performance.
Other research shows that among subjects with comparable APOE ε4 or amyloid burden, those with better memory were less likely to progress to mild cognitive impairment (MCI) or dementia. Conversely, another study comparing AD PRSs failed to show significant differences between SuperAgers and controls of a similar age group, though most participants were of European origin.
It thus remains unclear whether lower inherited AD risk is a marker of superior cognitive aging in older adults.
To help fill this gap, the current study used the multisite SuperAging Research Initiative. These researchers sought to evaluate whether exceptional cognitive aging in SuperAgers is attributable solely to lower inherited AD risk. They also evaluated whether genetic ancestry modified the relationship between inherited AD genetic risk and SuperAger status.
Comparing SuperAgers with typical older adults
The study included 142 SuperAgers and 89 cognitively average older adults (controls) recruited across five sites in the US and Canada. The groups were comparable in age and ancestry, although women made up a larger proportion of the SuperAger group. The statistical analyses adjusted for age, sex, and education.
The researchers examined the patterns of APOE as well as three PRSs that capture the combined effects of thousands of common genetic variants associated with Alzheimer's risk.
Genetic risk scores were similar across both groups
The findings show that APOE status (APOE ε2, ε3, and ε4 alleles) and PRSs were comparable between SuperAger and control subgroups.
For instance, approximately 16% of SuperAgers carried one or more ε4 alleles, compared with 19% of controls. Similarly, about 13% of both SuperAgers and controls carried at least one potentially protective ε2 allele. The mean PRS values were also comparable.
Moreover, the researchers found that the findings remained unchanged after accounting for genetic ancestry, with no evidence that ancestry modified the relationship between the genetic risk measures and SuperAger status.
Further exploratory analyses were performed to identify associations between the 768 variants common to the three PRSs. The findings showed no associations between any of the variants and SuperAger status after correcting for multiple testing.
The researchers also examined previously identified rare genetic variants that may offer protection against Alzheimer's disease. They found that one SuperAger carried the rare protective PLCG2 P522R variant, but there was no evidence that the protective variants examined were enriched among SuperAgers.
Other potential contributors
Although APOE and these polygenic risk scores are well-established markers that distinguish people with Alzheimer's disease from cognitively healthy adults, the genetic risk profiles did not distinguish SuperAgers from cognitively normal controls.
Lower inherited AD risk at the group level is a shared feature of successful cognitive aging into advanced age, but it is not sufficient to explain the exceptional memory performance that defines the SuperAging phenotype.
Study authors
SuperAging does not appear to be simply the opposite of dementia in terms of common genetic risk. Rather, the researchers suggest that multiple converging biological and experience-related factors contribute to this phenotype. These potentially include better neural preservation, vascular health, physical activity, and other lifestyle or experiential factors that may help buffer aging-related cognitive decline despite common genetic risk.
These potential resilience mechanisms are not captured by conventional genetic risk profiles for AD. However, the study revealed a few SuperAgers with elevated AD genetic risk, making them promising targets for detailed study of such mechanisms.
The study also did not assess Alzheimer's disease pathology using biomarkers such as amyloid or tau, so it could not determine whether SuperAgers remained cognitively resilient despite underlying pathology or had avoided it altogether.
Study lacked lifestyle and Alzheimer's biomarker data
The study used rigorous methodologies to define SuperAgers and controls, model ancestry, and optimize PRS cut-offs. However, it had some limitations.
The sample was too small to detect small genetic effects or examine ancestry-specific effects within the groups. Because the study was cross-sectional, the authors could not determine how inherited genetic risk relates to changes in cognition over time.
Behavioral and vascular factors were not included, though they may influence the SuperAger phenotype. The authors also noted that polygenic risk scores developed largely from European-ancestry datasets may not perform equally well across different ancestral groups.
SuperAging appears driven by more than genetics
The findings suggest that SuperAging and Alzheimer's disease risk are not simply two ends of the AD risk spectrum. Specific biological and experiential factors may play a role in preserving exceptional cognitive function into late life.
To distinguish the effects of AD pathology from resilience and the interaction between the two factors, larger longitudinal studies with more diverse populations are required. They should incorporate genetic risk variants, lifestyle factors, and AD pathology markers.
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Journal reference:
- Piras, I. S., Capuano, A. W., The SuperAging Research Initiative, et al. (2026). SuperAging is not the inverse of common-variant Alzheimer’s risk: evidence across genetic ancestries. Alzheimer’s Disease & Therapy.DOI: https://doi.org/10.1186/s13195-026-02124-2. https://link.springer.com/article/10.1186/s13195-026-02124-2