Researchers have discovered that individuals who live to be 100 years old and remain cognitively healthy possess genetic variations that may protect against Alzheimer’s disease. These “protective alleles” are significantly more prevalent among centenarians compared to Alzheimer’s patients and even middle-aged individuals without the disease. This finding could pave the way for new approaches in preventing and treating Alzheimer’s, particularly by focusing on enhancing these protective genetic mechanisms.
The new findings have been published in the journal Alzheimer’s & Dementia.
Alzheimer’s disease is a progressive neurological disorder that predominantly affects older adults, leading to a decline in cognitive functions such as memory and reasoning. Over time, this can result in a complete loss of independence and eventually death. The risk of developing Alzheimer’s increases significantly with age, and while it is not an inevitable part of aging, it is one of the most common causes of dementia among seniors.
The global population of individuals aged 100 years and older is rapidly increasing, with projections suggesting that there will be over 3 million centenarians worldwide by 2050. Remarkably, a subset of these individuals not only reaches this advanced age but does so while maintaining sharp cognitive functions. This exceptional group provides a unique opportunity to understand the factors that protect against Alzheimer’s disease, which could hold the key to longevity and healthy aging.
“Reaching extreme ages with maintained cognitive health tends to occur within families,” said study author Henne Holstege, an associate professor at the department of Human Genetics of the Amsterdam University Medical Center.
“I wanted to know which genetic elements were involved, to see what we can learn from those elements. What do they code for, and if we know which molecular mechanisms they regulate, can this be useful to learn from to help those who are at risk of dementia?”
“This is why I set up the 100-plus Study, a cohort study of cognitively healthy centenarians, and next to their DNA, we investigate their immune system, their gut microbiome, and some centenarians agree to post mortem brain donation, allowing us to get a holistic view of how potential protective genetic factors lead to a long and healthy life.”
A total of 6,747 individuals were included in the study. The sample comprised 2,542 Alzheimer’s patients, including those diagnosed clinically through neurological assessments and others confirmed pathologically. The control groups included 1,776 older adults from a longitudinal aging study, 1,524 adults who exhibited subjective cognitive decline but were found to be cognitively normal after thorough examination, and several smaller control groups, including 62 healthy controls and 196 participants from a twin study. Another crucial group comprised 360 centenarians from the 100-plus Study, who were verified as being cognitively healthy through both self-report and proxy reports.
Genetic analysis focused on 86 single nucleotide polymorphisms (SNPs), which are variations at a single position in DNA, previously associated with Alzheimer’s disease in genome-wide association studies (GWAS). To assess the significance of genetic findings, the study compared the frequency and impact of these SNPs across the different groups. This approach allowed researchers to pinpoint genetic variations that are either depleted or enriched in centenarians.
The analysis revealed several key genetic variations that differentiated cognitively healthy centenarians from Alzheimer’s patients and middle-aged controls.
One of the most significant findings was that cognitively healthy centenarians have a markedly lower polygenic risk score (PRS) for Alzheimer’s compared to both Alzheimer’s patients and middle-aged controls. The PRS, which aggregates the effects of 86 Alzheimer’s-associated genetic variants, was over five times lower in centenarians than in Alzheimer’s cases, and nearly twice as low compared to healthy middle-aged individuals. This suggests that centenarians possess a unique genetic profile that significantly reduces their risk of developing Alzheimer’s disease.
The findings indicate “that next to a healthy lifestyle, your genome also plays a substantial role in maintaining cognitive health while we age,” Holstege told PsyPost.
Among the protective genetic variants identified, the researchers highlighted alleles in genes such as ANKH, GRN, TMEM106B, and SORT1. These genes are implicated in maintaining brain health and are known to be involved in immune function and cellular waste management.
For instance, ANKH is associated with vascular health, while GRN, TMEM106B, and SORT1 play roles in the endolysosomal system, crucial for the brain’s ability to clear out potentially harmful waste. The significant enrichment of protective alleles in these genes among centenarians suggests that maintaining these genetic functions is essential for cognitive health in old age.
“We see that cognitively healthy centenarians are specifically enriched with genetic variants associated with the endolysosomal system and the immune system,” Holstege said. “Apparently, reaching 100 years in cognitive health depends on a the maintained function of these systems.”
This study highlights the potential of genetic research in uncovering the secrets to longevity and cognitive health. But the study, like all research, has limitations. The centenarians’ unique genetic traits might not only be protective against Alzheimer’s but could also contribute to broader aspects of health and longevity that are not solely focused on cognitive decline. Additionally, the study’s participants were primarily of European descent, which might limit the applicability of the findings to other populations.
“Here we tested the genetic regions that are more prevalent in Alzheimer’s disease compared to healthy individuals,” Holstege explained. “However, these are large stretches of DNA. Why these stretches of DNA are important is unclear, and we are working on finemapping these regions to get a better understanding of how these genetic regions might impact the downstream cellular regulation.”
“My long term goal is to get a good grip on how time differentially impacts each and everyone of us, each with our own unique vulnerabilities. In this, genetics plays an important role. Understanding the downstream differences from the genetic constellation that centenarians carry, compared to that from ‘normal’ individuals, will provide a wealth of information on what which molecular pathways we need to focus on to help others achieve the same.”
The study, “Cognitively healthy centenarians are genetically protected against Alzheimer’s disease,” was authored by Niccolo’ Tesi, Sven van der Lee, Marc Hulsman, Natasja M. van Schoor, Martijn Huisman, Yolande Pijnenburg, Wiesje M. van der Flier, Marcel Reinders, and Henne Holstege.
