The Genetic Advantage that Helps Some People Stay Mentally Fit Throughout their Lives

Among the known genetic factors associated with late-onset Alzheimer’s disease (AD), one gene variant stands out as the strongest risk factor. This variant is APOE-ε4. Another form of the same gene, APOE-ε2, is associated with a lower likelihood of developing Alzheimer’s and is generally considered to offer some protection against the disease. A large-scale study published in Alzheimer’s & Dementia, the journal of the Alzheimer’s Association, examined how often these two gene variants occur in a rare group known as “super agers.” Super agers are people aged 80 or older whose memory and thinking skills are similar to those of adults 20 or 30 years younger. The research was led by scientists at Vanderbilt University Medical Center.

Lower Frequency of the Alzheimer’s Risk Gene

The results showed a striking difference in genetic risk. Super-agers were 68% less likely to carry APOE-ε4 than individuals aged 80 and older who had Alzheimer’s dementia. Even more striking was the comparison with cognitively healthy peers. Super seniors were still 19% less likely to carry APOE-ε4 than other adults in the same age group who showed normal cognitive aging. APOE-ε4 is best known for being associated with an increased risk of Alzheimer’s dementia. People with one ε4 allele have a higher than average risk of developing the disease, while people with two ε4 alleles have a significantly higher risk. However, this does not mean that they will definitely develop the disease, but merely that there is a statistical increase in risk. Many carriers of APOE-ε4 remain mentally healthy throughout their lives.

“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 very elderly adults with a reduced genetic risk for Alzheimer’s disease,” said Dr. Leslie Gaynor, assistant professor of medicine in the Division of Geriatrics. She led the study together with Alaina Durant, BS, a statistical genetics analyst at the Vanderbilt Memory and Alzheimer’s Center.

Higher Concentrations of a Protective Gene Variant

The researchers discovered another important genetic difference. For the first time, it was demonstrated that super-agers have a higher frequency of APOE-ε2, the gene variant associated with a reduced risk of Alzheimer’s disease. APOE-ε2 is a variant of the APOE gene (apolipoprotein E), which plays an important role in fat metabolism and in the brain. APOE is responsible for transporting cholesterol and other fats in the body and supports repair and protective mechanisms of nerve cells in the brain.

There are three common variants of this gene: ε2, ε3, and ε4, with each person carrying two of these variants. Compared to the other variants, APOE-ε2 is generally considered to be more protective, especially with regard to the risk of Alzheimer’s dementia, which is lower in carriers of ε2 than in carriers of ε3 and, above all, ε4. In addition, APOE-ε2 is often associated with lower LDL cholesterol levels. Compared to cognitively normal adults aged 80 and older, super agers were 28% more likely to carry APOE-ε2. Compared to participants aged 80 or older who had Alzheimer’s dementia, super agers were 103% more likely to have this protective variant.

How Super-Agers Were Defined

This observational study included the largest number of super-seniors studied to date. The analysis was based on data from the Alzheimer’s Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC), led by study co-author Timothy Hohman, PhD, professor of neurology. In total, genetic and clinical data from 18,080 participants from eight national age cohorts were evaluated in the study. Super senior status was determined in part by memory performance. Participants aged 80 or older qualified if their memory scores were above the average for cognitively normal adults aged 50 to 64.

The study population included participants from various ethnic groups. Among them were 1,412 non-Hispanic white super seniors and 211 non-Hispanic black super seniors. The data set also included 8,829 individuals with AD dementia and 7,628 cognitively normal control subjects. Worldwide, the APOE-ε4 variant occurs in about 13.7% of people. Within this study population, the frequency was significantly higher at 43.9%.

Why Super-Agers are Important for Alzheimer’s Research

“Given the growing interest in super-agers,” Gaynor said, “our findings confirm the view that the super-ager phenotype will be useful in the ongoing search for mechanisms that confer resilience to AD. This is the largest study to date to identify differences in APOE ε4 allele frequency based on super-ager status, and the first study to find an association between APOE ε2 allele frequency and super-ager status. We expect these findings to further stimulate interest in questions such as how these variants may influence the development of clinical dementia due to Alzheimer’s disease, as well as the super-ager phenotype in general.”

Prevention research is also increasingly coming into focus. Studies show that lifestyle factors such as exercise, healthy eating, mental activity, social interaction, and control of cardiovascular risks can influence the risk of developing the disease. Overall, Alzheimer’s research is moving away from a single cause toward a multifactorial understanding that considers genetic, biological, and environmental factors together.