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Superagers' Exceptional Memory Can't Be Explained by Genes Alone, Study Finds
Inherited Alzheimer's risk didn't differ between superagers and cognitively average older adults
Key Takeaways
- Superagers are a group of people age 80 or older with episodic memory at least as good as adults 20 or 30 years younger.
- Why superagers have exceptional memory still isn't clear after two decades of research.
- This study showed that inherited Alzheimer's risks didn't differ between superagers and cognitively average controls, suggesting genes alone do not account for differences.
Exceptional memory at age 80 and beyond was not due simply to good genes, an analysis of prospective data suggested.
The study assessed outcomes for superagers -- people 80 or older with episodic memory at least as good as adults 20 or 30 years younger -- and cognitively average controls.
Genotype distributions and APOE status did not differ between groups, reported Ignazio Stefano Piras, PhD, of the Translational Genomics Research Institute at City of Hope in Phoenix, and co-authors.
Neither APOE nor any of three polygenic risk scores predicted whether a person would be a superager, Piras and colleagues wrote in Alzheimer's Research & Therapy. Results were similar after accounting for global non-European or African ancestry.
"For many years, aging research has focused on identifying factors that increase the risk of disease," Piras said in a statement. "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."
Alzheimer's disease is associated with the APOE gene, with APOE4 increasing risk and APOE2 generally conferring protection. Research has shown that superagers have a lower frequency of APOE4 and higher frequency of APOE2 alleles compared with other older adults.
Two decades of research have identified biological and social characteristics associated with superagers: they maintained good brain morphology, tended to be gregarious, and appeared to be resistant to neurofibrillary degeneration and resilient to its consequences. Unlike neurotypical peers, superagers had a region in the cingulate gyrus that was thicker than younger adults. They had fewer Alzheimer's-related brain changes, greater size of entorhinal neurons, fewer inflammatory microglia in white matter, and better-preserved cholinergic innervation.
But an underlying question remained: Could superagers simply be people with little genetic risk for Alzheimer's?
"If that were true, identifying superagers might be as simple as performing genetic testing rather than the comprehensive cognitive evaluations we currently use," said co-author Emily Rogalski, PhD, of the Healthy Aging and Alzheimer's Research Care Center at the University of Chicago.
To test whether a lower inherited risk of Alzheimer's disease dementia predicted superager status, Piras and colleagues studied prospectively enrolled superagers and cognitively average controls from the SuperAging Research Initiative. They assessed APOE2, APOE3, and APOE4 status and three Alzheimer's disease polygenic risk scores derived from large contemporary genome-wide association studies.
At enrollment, participants were age 80 or older, had no neurologic disorders known to affect cognition, and had no significant uncontrolled medical conditions. They were classified as superagers or controls based on a priori cognitive criteria that included exceptional episodic memory performance. All superagers and controls had a Clinical Dementia Rating score equal to zero, indicating no clinical impairment in either group.
The study included 142 superagers and 89 controls from five regional sites in the U.S. and Canada. Superagers had a mean age of 83.7 years and controls had a mean age of 84.7. The genetic ancestry structure across both groups was comparable.
Groupwise comparisons of APOE status did not differ significantly between superagers and controls. In models adjusted for age, sex, and years of education, APOE2, APOE3, and APOE4 allele status were not associated with odds of superager classification. Proportions of participants with at least one APOE2 allele (superagers 12.7% vs controls 13.1%) or at least one APOE4 allele (superagers 15.7% vs controls 19.0%) were similar across groups.
None of the three Alzheimer's disease polygenic risk scores -- PRSLambert, PRSWightman, or PRSBellenguez -- were associated with odds of superager classification. An analysis of rare protective variants including the APP Icelandic variant, the PLCG2 P552R variant, and the APOE Christchurch variant identified one heterozygous superager carrying the PLCG2 P522R variant in the study. No other rare mutation carriers were seen in either the superager or control group.
While APOE allele frequencies and polygenic risk scores did not distinguish superagers from cognitively average older adults, both groups differed meaningfully from individuals with Alzheimer's disease, who are more likely to have these genetic risk factors, Piras and co-authors noted.
"This pattern indicates that lower inherited Alzheimer's disease 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," they stated.
The study's limitations included modest power for small genetic effects, the researchers acknowledged. The analyses did not incorporate vascular, lifestyle, or behavioral factors, which may contribute to superaging and represent an important direction for future research, they added.
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