Increased Genetic Protection Against Alzheimer’s Disease in Centenarians
Do people who live to extreme old ages have special genetic protection against Alzheimer's disease that most of us don't have?
College of Health researcher(s)
College unit(s)
Abstract
We constructed a polygenic protective score specific to Alzheimer’s disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the US, Europe, and Asia. This AD PPS did not include variants on Apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality. Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.
FAQ: Genetic Protection Against Alzheimer's Disease in Centenarians
What is the main objective of this study regarding Alzheimer's Disease (AD) and centenarians?
The primary objective of this study was to investigate the genetic protection against Alzheimer's disease (AD) in centenarians (individuals aged 100 years and older). Researchers constructed a polygenic protective score specific to AD (AD PPS), excluding variants on the APOE gene, and compared this score across different age groups and populations. The goal was to determine if centenarians exhibit stronger genetic protection against AD compared to younger individuals without familial longevity and to see if this protection increases with advancing age among centenarians. The study also examined the correlation between a higher AD PPS and better cognitive function and decreased mortality.
What is a Polygenic Protective Score (AD PPS) and how was it developed in this study?
A Polygenic Protective Score (AD PPS) is a measure that aggregates the effect of multiple genetic loci (specific locations on a gene) that are associated with a decreased risk of developing Alzheimer's disease. In this study, the AD PPS was constructed based on a list of 83 genetic variants identified in a large-scale GWAS (Genome-Wide Association Study) meta-analysis. Importantly, the well-known APOE gene variants, which are also strongly linked to AD, were intentionally excluded from this specific AD PPS calculation to explore other protective genetic factors. The score was calculated by summing up the "protective alleles" (gene variants that reduce the odds of having AD) present in an individual's genome. The exact number of variants used varied slightly across different study cohorts due to data availability.
Which populations and cohorts were included in this research?
This study included participants from five major studies of healthy aging and extreme longevity spanning different geographical and genetic backgrounds:
- New England Centenarian Study (NECS): Based in North America, including centenarians, their siblings, offspring, offspring spouses, and unrelated controls.
- Long Life Family Study (LLFS): A family-based study of healthy aging and longevity with participants from the United States (Danish site data excluded).
- Longevity Genes Project (LGP) / LonGenity Study: Consisted of Ashkenazi Jewish centenarians, their offspring, and controls in the United States.
- Tokyo Centenarian Study (TCS) and Japan Semisupercentenarian Study (JSS): Two prospective cohort studies of the oldest individuals in Japan.
- 100-plus Study: Included cognitively healthy Dutch-speaking individuals aged 100 years or older.
These diverse cohorts allowed the researchers to test the robustness of their findings across different genetic backgrounds.
What was the key finding regarding genetic protection against AD in centenarians compared to younger individuals?
A significant finding was that centenarians generally exhibit stronger genetic protection against AD compared to individuals without familial longevity (study controls). In the NECS, centenarians and their offspring had significantly higher AD PPS than controls. Similar patterns were observed in the LLFS and 100-plus Study, where centenarians showed a higher AD PPS than controls. This suggests that possessing more of these protective genetic variants contributes to the ability to reach extreme old age.
Does genetic protection against AD increase with extreme older ages, even beyond 100 years?
Yes, the study provides evidence that genetic protection against AD increases with increasingly older ages, particularly among centenarians. In the NECS, a clear increasing trend in the mean AD PPS was observed from nonagenarians (ages 90-99) to centenarians (100-104), semi-supercentenarians (105-109), and supercentenarians (110+). Specifically, semi-supercentenarians and supercentenarians had significantly higher AD PPS than centenarians. Similar trends, though not always statistically significant due to smaller sample sizes in the older age groups of some cohorts, were seen in the LLFS, LGP, and TCS/JSS. This implies that those who achieve the most extreme ages, on average, possess even greater genetic protection against AD.
How does a higher AD PPS relate to cognitive function and mortality?
The study found that a higher AD PPS was associated with better cognitive function and decreased mortality, especially in centenarians. In the NECS, a significant association was detected between higher AD PPS and better scores on the Blessed Information-Memory-Concentration (BIMC) test among centenarians, indicating better cognitive abilities. In the LLFS, a higher AD PPS was associated with slower cognitive decline over time (based on TICS scores and logical memory recall). Furthermore, a higher AD PPS was significantly associated with a lower hazard ratio for mortality (meaning a lower risk of death) in both the NECS and LLFS, particularly driven by the centenarian group. This suggests that these protective genetic factors contribute not only to a reduced risk of AD but also to a longer, healthier life.
What is surprising about the magnitude of this genetic protection, and what might it imply?
A surprising finding was that the magnitude of the increase in AD PPS with age was quite modest. For example, in the NECS, the average increase from nonagenarians to supercentenarians was only about one to two additional protective alleles. This suggests that even a small genetic advantage in terms of protective alleles may have a substantial effect on delaying morbidity and reducing AD risk, allowing individuals to reach extreme old age. The researchers conjecture that the AD PPS likely represents only one component of genetic protection, and centenarians' genomes may harbor additional, perhaps rare, genetic variants not yet fully understood or included in current scores. This points to the need for further research to identify a more complete catalogue of genetic protections against AD.
What are the broader implications of these findings, particularly for therapeutics?
The findings have important implications, especially for the universal applicability of future therapeutics. By showing that this genetic protection is robust across different genetic backgrounds (US, European, and Asian cohorts), the study suggests that therapies targeting the pathways influenced by these protective genetic variants could potentially benefit a wide range of populations. It highlights the value of studying individuals with extreme longevity as models for understanding resilience to age-related diseases like AD. While the identified genetic protection is modest in size, it opens avenues for identifying and understanding new protective mechanisms, potentially leading to novel therapeutic strategies to delay or prevent AD.