Study finds so-called super agers tend to have at least two key genetic advantages

The gene variant posing the greatest genetic risk of late-onset Alzheimer's disease (AD) is called APOE-ε4. A different variant of the same gene, APOE-ε2, is thought to confer protection against AD.

 

A comparatively large study reported Jan. 16 in Alzheimer's & Dementia, The Journal of the Alzheimer's Association, led by researchers at Vanderbilt University Medical Center, measures the frequency of APOE-ε4 and APOE-ε2 in so-called super agers — people ages 80 or older whose cognitive function is comparable to people 20 or 30 years younger.

 

Super agers were 68% less likely to harbor the gene nobody wants, APOE-ε4, compared to individuals with AD dementia in the same 80+ age group.

 

Most notably, super agers were 19% less likely to harbor APOE-ε4 than were cognitively normal participants in the same age group. 

 

"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 super-ager phenotype can be used to identify a particularly exceptional group of oldest-old adults with a reduced genetic risk for Alzheimer’s disease," said Leslie Gaynor, PhD, assistant professor of Medicine in the Division of Geriatric Medicine, who led the study with Alaina Durant, BS, statistical genetic analyst in the Vanderbilt Memory and Alzheimer's Center. 

 

Super agers were also found for the first time to have higher frequency of the variant you'd want, APOE-ε2: They were 28% more likely to carry APOE-ε2 than were cognitively normal controls ages 80+, and 103% more likely to carry the variant than were participants with AD dementia aged 80 or older. 

 

The observational study, which includes the largest sample of super agers to date, uses data from the Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC), led by another member of the study team, Timothy Hohman, PhD, professor of Neurology. The study included 18,080 participants from eight national aging cohorts.

 

Super-ager status was defined in part as people ages 80+ whose memory performance was above the average scored among cognitively normal participants ages 50 to 64. The study included multiple race/ethnicity groups, including 1,412 non-Hispanic white super agers, 211 non-Hispanic Black super agers, 8,829 participants with AD dementia, and 7,628 cognitively normal controls. APOE-ε4 frequency worldwide is 13.7%; in the study it was 43.9%. 

 

"With interest in super agers growing," Gaynor said, "our findings notably encourage the view that the super-ager phenotype will prove useful in the continued search for mechanisms conferring resilience to AD.

 

"This is by far the largest study to date to identify differences in APOE-ε4 allele frequency based on super-ager status, and the first study to find a relationship between APOE-ε2 allele frequency and super-ager status. 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 super-ager phenotype more generally."

 

Others from VUMC on the study include Angela Jefferson, PhD, Logan Dumitrescu, MS, PhD, and Derek Archer, PhD. They were joined by 32 researchers from 15 universities. The study was funded in part by National Institutes of Health awards U24 AG074855, U01 AG068057, and R01 AG059716.

 

 

 

 

---

---