The genetic advantage that helps some people stay sharp for life
Among the known genetic factors tied to late-onset Alzheimer’s disease (AD), one gene variant stands out as the strongest
Among the known genetic factors tied to late-onset Alzheimer’s disease (AD), one gene variant stands out as the strongest risk factor. That variant is APOE-ε4. Another form of the same gene, APOE-ε2, has been associated with a lower likelihood of developing Alzheimer’s and is widely believed to offer some level of protection against the disease.
A large study published Jan. 16 in Alzheimer’s & Dementia, The Journal of the Alzheimer’s Association, set out to examine how often these two gene variants appear in a rare group known as super agers. Super agers are people age 80 or older whose memory and thinking abilities closely resemble those of adults who are 20 or 30 years younger. The research was led by investigators at Vanderbilt University Medical Center.
Lower Frequency of Alzheimer’s Risk Gene
The results showed a striking difference in genetic risk. Super agers were 68% less likely to carry APOE-ε4 when compared with individuals age 80 and older who had Alzheimer’s dementia.
What stood out even more was the comparison with cognitively healthy peers. Super agers were still 19% less likely to carry APOE-ε4 than other adults in the same age group who showed normal cognitive aging.
“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. She led the study together with Alaina Durant, BS, a statistical genetic analyst in the Vanderbilt Memory and Alzheimer’s Center.
Higher Levels of a Protective Gene Variant
Researchers also discovered another important genetic distinction. For the first time, super agers were shown to have a higher frequency of APOE-ε2, the gene variant linked to reduced Alzheimer’s risk.
Compared with cognitively normal adults age 80 and older, super agers were 28% more likely to carry APOE-ε2. When compared with participants age 80 or older who had Alzheimer’s dementia, super agers were 103% more likely to have this protective variant.
Largest Study of Super Agers to Date
This observational study included the largest number of super agers examined so far. The analysis drew on data from the Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC), which is led by study co-author Timothy Hohman, PhD, professor of Neurology.
Altogether, the study evaluated genetic and clinical data from 18,080 participants across eight national aging cohorts.
How Super Agers Were Defined
Super ager status was partly determined by memory performance. Participants age 80 or older qualified if their memory scores were higher than the average score among cognitively normal adults ages 50 to 64.
The study population included participants from several race and ethnicity groups. Among them were 1,412 non-Hispanic white super agers and 211 non-Hispanic Black super agers. The dataset also included 8,829 individuals with AD dementia and 7,628 cognitively normal controls.
Worldwide, the APOE-ε4 variant is found in about 13.7% of people. Within this study population, the frequency was much higher at 43.9%.
Why Super Agers Matter for Alzheimer’s Research
“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.”
Research Team and Funding
Additional contributors from Vanderbilt University Medical Center included Angela Jefferson, PhD, Logan Dumitrescu, MS, PhD, and Derek Archer, PhD. They worked alongside 32 researchers from 15 universities.
The study was supported in part by National Institutes of Health awards U24 AG074855, U01 AG068057, and R01 AG059716.
