Centenarian Study Uncovers Gene Variants That Shield Against Alzheimer’s

Reviewed by Sharyn Rossi, PhD, BrightFocus Foundation

People who reach age 100 with little or no signs of cognitive decline are lucky, to be sure. Just how they’re able to resist aging-related diseases, like Alzheimer’s, is still a mystery. A new study funded by BrightFocus Foundation’s Alzheimer’s Disease Research program suggests these centenarians may have genetic protection that supports healthy brain aging. Findings from this study could uncover specific genetic variants or resilience associated pathways that can be targeted to help prevent cognitive decline in those at risk of developing Alzheimer’s.    

The research team was led by Alzheimer’s Disease Research grant recipient Henne Holstege, PhD, an assistant professor in the Department of Human Genetics at Amsterdam University Medical Center. The study, published in Alzheimer’s & Dementia, builds on previous research by Dr. Holstege, who spearheaded and instituted a cohort of cognitively healthy centenarians in the Netherlands for clues into resistance against Alzheimer’s. 

The study uncovered an association between the long-term maintenance of cognitive health and several single nucleotide polymorphisms—or genetic variants—that are linked to Alzheimer’s risk. The researchers found that people who reach age 100 without showing signs of Alzheimer’s are enriched with genetic variants that help protect the brain from amyloid plaques and other hallmarks of the disease. 

Dr. Holstege’s team set out to determine the prevalence of 86 known Alzheimer’s-related genetic variants in cognitively healthy centenarians. Because the genetic factors behind long-term resistance to the disease are largely unknown, they focused on investigating the individual and combined effects of the variants on prolonged brain health. 

The study centered around data and samples collected from 6,747 people, about one-third of whom had been diagnosed with Alzheimer’s. The rest of the study population consisted of individuals who were cognitively healthy and the same age.  

Balancing Risk Reduction With Protection  

Dr. Holstege and her fellow researchers focused on different versions, or “alleles,” of the Alzheimer’s-associated genetic variants. In Alzheimer’s, there are alleles that raise risk due to harmful factors such as poor vasculature in the brain, as well as protective alleles that shield against amyloid buildup and other disease characteristics.  

“Cognitively healthy centenarians have a lower frequency of almost all risk-increasing alleles and a higher frequency of protective alleles,” the researchers wrote in the study. Maintaining cognitive health, therefore, depends on having the perfect balance of all genetic variations associated with the disease, they added.  

Specifically, Dr. Holstege’s team found that cognitively healthy centenarians have significantly lower levels of three risk alleles and higher levels of four protective alleles than their counterparts. The effect across all seven alleles—the relationship between the genetic variations and cognitive protection—was amplified four-fold among cognitive healthy centenarians as compared to Alzheimer’s patients, the researchers reported.  

When the team delved into the specific characteristics of the seven key alleles, they determined that they are critical to maintaining immune system responses and waste clearance mechanisms that effectively process and recycle toxic proteins like amyloid-beta and tau. The findings demonstrate the most important mechanisms behind resilience to Alzheimer’s, the researchers wrote. 

Continued Learning from Centenarians 

The research participants included 360 centenarians from Dr. Holstege’s 100-Plus Study, a cohort of Dutch centenarians who have high brain function. Previous research found that many centenarians do not suffer cognitive impairment despite the presence of amyloid plaques and other pathologies in their brains. 

In a prior study, Dr. Holstege and her colleagues found that brains donated by healthy centenarians showed amyloid plaques in many regions, but these did not result in disease. This suggests that protective alleles are processing and clearing amyloid in a way that prevents it from accumulating in the brain, they said. 

The authors noted some limitations of the study, including their inability to compare healthy centenarians to centenarians with Alzheimer’s. The homogeneous nature of the study population—all were Dutch—might also have biased the results, given that genetic associations to Alzheimer’s may vary in people of different ancestries, the authors added.  

Still, they concluded that their findings demonstrate the value of further investigation into genetic variants that protect brain functioning over the long term. It’s all part of Holstege’s overall mission to unlock the genetic processes that drive Alzheimer’s, in the hopes of improving the search for new treatments and, in the future, predicting who is at risk of the disease long before they develop symptoms. 

Additional Resources: 

• Watch: The Role of Genetics in Early Diagnosis and Treatment of Dementia  
• Brain Health and Alzheimer’s Disease 
• Healthy Aging and Cognitive Reserve 
• Watch: Can Non-Drug Interventions Really Reduce Your Risk of Alzheimer’s? 
• Watch: Can Alzheimer’s Be Prevented? 

About BrightFocus Foundation        

BrightFocus Foundation is a premier global nonprofit funder of research to defeat Alzheimer’s, macular degeneration, and glaucoma. Through its flagship research programs — Alzheimer’s Disease Research, National Glaucoma Research, and Macular Degeneration Research — the Foundation has awarded nearly $300 million in groundbreaking research funding over the past 51 years and shares the latest research findings, expert information, and resources to empower the millions impacted by these devastating diseases. Learn more at brightfocus.org. 

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