Genetic Factors in Extreme Longevity
Recent studies have expanded our understanding of the genetic basis for exceptional longevity and cognitive resilience in centenarians:
Protective Genetic Variants
Researchers have identified several genetic variants that appear to protect against Alzheimer’s disease and cognitive decline in extremely old individuals:
- The R251G mutation in the APOE gene reduces Alzheimer’s risk by up to 70% in people carrying the high-risk APOE4 variant.
- The V236E mutation, co-inherited with APOE3, decreases Alzheimer’s risk by about 60%.
- Cognitively healthy centenarians are enriched with protective alleles of genes involved in the immune and endolysosomal systems, including ANKH, GRN, TMEM106B, SORT1, PLCG2, and RIN3.
Polygenic Risk Scores
Centenarians who maintain cognitive health have significantly lower polygenic risk scores for Alzheimer’s disease:
- Over 5-fold lower than Alzheimer’s patients
- About 2-fold lower than age-matched controls
Insights from Exceptional Cases
Studies of rare individuals with genetic predispositions for early-onset Alzheimer’s who remain cognitively intact into old age have provided valuable insights:
- A man with the “Paisa” mutation (Presenilin-1 E280A) remained cognitively intact until age 67, decades beyond the typical onset age.
- These cases point to protective pathways that may confer extreme resilience against Alzheimer’s symptoms.
Implications for Research and Treatment
These findings are shaping new directions in Alzheimer’s research and potential therapies:
- Targeting the fibronectin gene and blood-brain barrier for drug development.
- Focusing on the endolysosomal and immune systems as key areas for intervention.
- Identifying specific brain regions that may be optimal targets for future treatments.
The genetic sequencing of extremely long-lived individuals continues to provide valuable data for understanding the biological mechanisms of longevity and cognitive resilience. This research offers promising avenues for developing new strategies to prevent or delay age-related cognitive decline and Alzheimer’s disease.
Read More
[1] https://www.cuimc.columbia.edu/news/newly-found-genetic-variant-defends-against-alzheimers-disease
[2] https://med.stanford.edu/news/all-news/2022/05/gene-mutation-alzheimers.html
[3] https://pubmed.ncbi.nlm.nih.gov/38634500/
[4] https://hms.harvard.edu/news/newly-identified-genetic-variant-protects-against-alzheimers
[5] https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/alzheimers-disease-genetics-fact-sheet
[6] https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-genes/art-20046552
[7] https://www.bbc.com/news/health-15278823
