A comprehensive investigation involving over 18,000 individuals has uncovered that “SuperAgers” – individuals exhibiting remarkable resistance to dementia in their advanced years – possess at least two significant genetic predispositions.
This cohort of adults aged 80 and above not only demonstrates a considerably lower probability of carrying a genetic variant linked to an elevated risk of Alzheimer’s disease but also shows a greater likelihood of inheriting a variant associated with a reduced risk.
This outcome suggests that while genetic factors are by no means the sole determinant, exceptional memory in later life is, to a certain extent, encoded within the genome of SuperAgers.
“This was our most compelling discovery,” states neuropsychologist Leslie Gaynor from Vanderbilt University Medical Center in the United States.
“Although all adults reaching the age of 80 without a clinical dementia diagnosis exhibit exceptional aging, our research indicates that the SuperAger phenotype can be utilized to pinpoint a particularly distinguished group of the very elderly who have a diminished genetic predisposition to Alzheimer’s disease.”
SuperAgers represent a segment of the population whose memory capabilities can be best characterized as outstanding within their age group, rivaling those of individuals decades younger.
However, this distinction is not confined to cognitive acuity alone. SuperAgers also appear substantially less prone to developing dementia compared to the general populace. Researchers are keen to understand the underlying mechanisms of this phenomenon, as it may offer crucial insights into the processes involved in dementia and potential strategies for its delay and mitigation.
“With mounting interest in SuperAgers,” Gaynor comments, “our findings strongly support the notion that the SuperAger phenotype will prove invaluable in the ongoing quest to identify the mechanisms that confer resilience against Alzheimer’s disease.”
It is widely acknowledged that the ε4 variant of the Apolipoprotein E (APOE) gene stands as the most significant known genetic risk factor for Alzheimer’s disease, a neurodegenerative disorder for which no cure exists, characterized by progressive cognitive decline typically manifesting in old age. Conversely, the APOE-ε2 gene variant is associated with a markedly reduced risk of Alzheimer’s disease.
Neuroimaging studies have revealed discrepancies in brain structure and its fortitude against the amyloid plaques implicated in Alzheimer’s between SuperAgers and the broader population. Gaynor, alongside her co-lead author, statistical genetic analyst Alaina Durant of Vanderbilt University Medical Center, and their colleagues, sought to investigate the role, if any, genetics plays in SuperAger status.
Their research involved an in-depth analysis of data gathered from 18,080 individuals across eight extensive aging studies conducted within the United States. These studies incorporated assessments of cognitive performance in the domains of memory, executive function, language, and visuospatial abilities, alongside genetic information collected from the participants.
The study defined SuperAgers as individuals aged 80 and above whose cognitive performance surpassed the average scores of cognitively healthy participants aged between 50 and 64. In total, the participant pool comprised 1,623 SuperAgers, 8,829 individuals diagnosed with Alzheimer’s disease, and 7,628 cognitively healthy control subjects.
Among the non-Hispanic White participants, who constituted the majority of the study cohort, the findings indicated that SuperAgers were 68 percent less likely to possess the APOE-ε4 variant compared to individuals with Alzheimer’s disease. Critically, they were 19 percent less likely to carry APOE-ε4 than age-matched cognitively healthy controls.
Furthermore, non-Hispanic White (NHW) SuperAgers exhibited a 103 percent higher prevalence of the protective APOE-ε2 allele when compared to NHW participants with Alzheimer’s disease, and a 28 percent greater likelihood compared to NHW cognitively healthy controls.
Although the limited sample of non-Hispanic Black individuals in this study mirrored similar trends, the researchers acknowledge the necessity for further investigations with a more substantial cohort of non-Hispanic Black SuperAgers to definitively ascertain whether resilience factors differ across populations.
These findings suggest that within certain demographic groups, SuperAgers do not circumvent Alzheimer’s through mere chance; rather, they are genetically distinct even from other individuals who experience healthy aging, with their genetic makeup inherently tilting the probabilities away from developing Alzheimer’s.
“This represents by far the most extensive study to date to identify variations in APOE-ε4 allele frequency in relation to SuperAger status, and it is the inaugural study to establish a correlation between APOE-ε2 allele frequency and SuperAger status,” stated Gaynor.
“We anticipate that these discoveries will sustain interest in exploring how these specific genetic variants might influence the onset of clinical dementia attributed to Alzheimer’s disease, as well as the broader SuperAger phenotype.”
