A massive study of more than 18,000 people has revealed that "SuperAgers" – people unusually resistant to dementia in older age – have at least two key genetic advantages.
Not only is this population of adults aged 80+ much less likely to carry a gene variant that's associated with higher Alzheimer's risk, but they're also more likely to carry one associated with lower risk.
It's a result that shows that, while genes are far from the only factor at play, exceptional memory in old age is at least partly written into the superager genome.
"This was our most striking finding," says neuropsychologist Leslie Gaynor of Vanderbilt University Medical Center in the US.
"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."
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Superagers are a population whose memories can best be described as exceptional among their demographic, rivalling those of people decades younger.
But it doesn't just manifest as cognitive sharpness. Superagers also appear far less likely to develop dementia than the general population. Scientists would like to know how this occurs, because it may offer insights into some of the mechanisms behind dementia, as well as possible strategies for delay and mitigation.
"With interest in superagers growing," Gaynor says, "our findings notably encourage the view that the superager phenotype will prove useful in the continued search for mechanisms conferring resilience to Alzheimer's disease."
It's well established that the ε4 variant of the gene Apolipoprotein E (APOE) is the strongest known genetic risk factor for Alzheimer's disease, a neurodegenerative condition with no known cure, characterized by a progressive loss of cognitive function, usually in old age. On the other hand, the gene variant APOE-ε2 is associated with a much lower risk of Alzheimer's disease.
Imaging studies have shown differences in the brain structure and its resistance to the amyloid plaques associated with Alzheimer's between SuperAgers and the rest of the population. Gaynor, her co-lead author, statistical genetic analyst Alaina Durant of Vanderbilt University Medical Center, and their colleagues wanted to study what role, if any, genetics plays in superager status.
Their research was based on an analysis of data collected from 18,080 people across eight large aging studies conducted in the US. These studies included tests of cognitive performance across the memory, executive function, language, and visuospatial domains, as well as genetic data collected from the participants.
The study defined superagers as those aged 80 and older whose cognitive performance exceeded the average score of cognitively normal participants aged 50–64. In total, the participants included 1,623 superagers, 8,829 people with Alzheimer's disease, and 7,628 cognitively normal controls.
Among non-Hispanic White people, who made up the majority of study participants, the results indicated that superagers were 68 percent less likely to carry APOE-ε4 than participants with Alzheimer's disease. Crucially, they were 19 percent less likely to carry APOE-ε4 than age-matched cognitively normal controls.
Meanwhile, non-Hispanic White (NHW) superagers were 103 percent more likely to carry the protective APOE-ε2 allele than NHW participants with Alzheimer's disease, and 28 percent more likely than NHW cognitively normal controls.
The small sample of non-Hispanic Black people in this study showed similar patterns, but the researchers acknowledge that we need more studies with a larger group of non-Hispanic Black superagers to properly determine if resilience factors vary by population.
The findings imply that in some populations, superagers don't avoid Alzheimer's by chance; they're genetically different even from other people who age well, with their genomes tilting the odds against Alzheimer's in their favor.
"This is by far the largest study to date to identify differences in APOE-ε4 allele frequency based on superager status, and the first study to find a relationship between APOE-ε2 allele frequency and superager status," Gaynor says.
"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 research has been published in Alzheimer's & Dementia.