The gene variant posing the greatest genetic risk for late-onset Alzheimer’s disease (AD) is known as APOE-ε4. In contrast, a different variant of the same gene, APOE-ε2, is believed to offer protection against AD. A significant study published on January 16 in Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association, led by researchers at Vanderbilt University Medical Center, has measured the frequency of APOE-ε4 and APOE-ε2 in individuals known as super agers—people aged 80 or older whose cognitive function is comparable to those 20 or 30 years younger.
The study reveals that super agers are 68% less likely to carry the APOE-ε4 gene compared to individuals with AD dementia in the same age group. Notably, super agers were also 19% less likely to carry APOE-ε4 than cognitively normal participants in the same age bracket.
“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 at the Vanderbilt Memory and Alzheimer’s Center.
Genetic Benefits of Super Agers
For the first time, the study found that super agers have a higher frequency of the protective variant APOE-ε2. They were 28% more likely to carry APOE-ε2 than cognitively normal controls aged 80 and older, and 103% more likely than participants with AD dementia in the same age group. This 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 Timothy Hohman, PhD, professor of Neurology.
The study encompassed 18,080 participants from eight national aging cohorts. Super-ager status was partly defined as individuals aged 80+ with memory performance above the average scored among cognitively normal participants aged 50 to 64. The research included multiple race and ethnicity groups, featuring 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. Globally, the APOE-ε4 frequency is 13.7%, while in the study, it was 43.9%.
Implications for Alzheimer’s Research
With growing interest in super agers, Gaynor emphasized that the findings support the notion that the super-ager phenotype could be instrumental in the ongoing search for mechanisms that confer resilience to AD. This study is the largest to date identifying differences in APOE-ε4 allele frequency based on super-ager status and the first to establish 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 the development of clinical dementia due to Alzheimer’s disease, as well as to the super-ager phenotype more generally,” Gaynor stated.
Additional contributors from Vanderbilt University Medical Center include Angela Jefferson, PhD, Logan Dumitrescu, MS, PhD, and Derek Archer, PhD. The study was a collaborative effort involving 32 researchers from 15 universities and was funded in part by National Institutes of Health awards U24 AG074855, U01 AG068057, and R01 AG059716.
Looking Ahead
The findings of this study could pave the way for further research into genetic factors that contribute to cognitive longevity. As the population ages, understanding the genetic underpinnings of super agers could inform strategies to combat Alzheimer’s disease and improve quality of life for older adults. Future research may focus on how these genetic variants interact with lifestyle and environmental factors to influence cognitive health.
As scientists continue to unravel the complexities of Alzheimer’s disease, the insights gleaned from studying super agers could offer hope for new preventative strategies and treatments. The ongoing exploration of genetic resilience in aging not only enhances our understanding of Alzheimer’s but also sheds light on the broader spectrum of aging and cognitive health.
