By Judy George

Superagers have the memory capacity of much younger people, but what drives this performance is unknown. This study found that the protective APOE2 allele occurred more frequently in superagers than in others. Superagers also had a lower frequency of the high-risk APOE4 allele compared with controls.

Superagers -- adults 80 and older with the memory capacity of much younger people -- had a higher frequency of gene variants that protected against Alzheimer's disease and a lower frequency of genes considered harmful, data from eight cohorts showed.

The odds of having a protective APOE2 allele were 28% higher in superagers compared with same-age controls (OR 1.28, 95% CI 1.03-1.59) and 103% higher in superagers versus people 80 or older with Alzheimer's dementia (OR 2.03, 95% CI 1.68-2.44), reported Leslie Gaynor, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee, and colleagues.

The odds of having an APOE4 allele -- the variant that carries the highest genetic risk of late-onset Alzheimer's disease -- was 19% lower in superagers compared with same-age controls (OR 0.81, 95% CI 0.67-0.99), Gaynor and co-authors wrote.

"This was our most striking finding -- although all adults who reach the age of 80 without receiving a diagnosis of clinical dementia exhibit exceptional aging, our study suggests that the superager phenotype can be used to identify a particularly exceptional group of oldest-old adults with a reduced genetic risk for Alzheimer's disease," Gaynor said in a statement.

"This is by far the largest study to date to identify differences in APOE4 allele frequency based on superager status, and the first study to find a relationship between APOE2 allele frequency and superager status," Gaynor observed. "We would expect these findings to lend continued interest to questions of how these variants may influence development of clinical dementia due to Alzheimer's disease, as well as to the superager phenotype more generally."

The APOE gene has three alleles -- APOE2, APOE3, and APOE4. All people have two APOE genes, leading to six possible combinations of variants.

In Alzheimer's disease, the most prevalent protective allele is APOE2, and people carrying at least one APOE4 allele have a higher risk of Alzheimer's disease. People who carry two APOE4 alleles have the highest risk.

Superagers is a term that generally describes adults 80 and older with episodic memory performance similar to that of people in midlife. What drives superagers' high memory scores is unknown, though both resistance to age-related pathology and resilience appear to be involved.

Previous studies that assessed APOE4 frequency in superagers have had small samples, and few studies have examined APOE2 frequency in superagers, the researchers noted.

Gaynor and colleagues evaluated data from 18,080 participants in eight national aging cohorts that were part of the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). They defined superagers in part as people ages 80 and up whose memory performance was above the average scored among cognitively normal participants ages 50 to 64.

Superagers made up 9% of the cohort. Participants included 1,412 white superagers, 211 Black superagers, 8,829 people with Alzheimer's disease dementia, and 7,628 cognitively normal controls.

The frequency of APOE variants differed between superagers and all Alzheimer's disease dementia cases, but varied between superagers and controls mainly in comparisons involving white older adults. Further research with larger samples of Black superagers is needed, the researchers pointed out.

The study had several other limitations, Gaynor and co-authors acknowledged. Participants were highly educated across cohorts and results might not apply to other populations.

Studies also have identified other genes that may confer greater Alzheimer's risk in Black populations compared with APOE, including ABCA7, the researchers noted. "Future studies will need to consider other genetic factors that may also be relevant to exceptional aging" in older Black adults, they wrote.