Observational and genetic studies of short telomeres and Alzheimer's disease in 67,000 and 152,000 individuals: a Mendelian randomization study.
Level 3 - non-randomized controlled study
Prospective observational cohort and Mendelian randomization (genetic instrumental variable) study.
PubMed 31564046 · doi:10.1007/s10654-019-00563-w
What was done
The authors examined the relationship between leukocyte telomere length and Alzheimer's disease using observational and Mendelian randomization approaches. Telomere length was measured in 66,567 individuals from two Copenhagen population-based studies. Genotyping was performed for three single nucleotide polymorphisms associated with telomere shortening (rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC) in 98,146 individuals from the Copenhagen studies, alongside genetic data from 54,162 individuals in the International Genomics of Alzheimer's Project.
What was found
Observationally, the multifactorially adjusted hazard ratio for Alzheimer's disease was 1.02 (95% CI 1.00-1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals carrying 6 versus 0-1 shortening alleles (p = 5 × 10^-105). Genetically, the odds ratio for Alzheimer's disease was 1.08 (95% CI 1.01-1.16) per 200 base pairs shorter telomeres. Genetically predicted shorter telomeres were also associated with increased risk of myocardial infarction and decreased risks of lung cancer and melanoma.
Why it matters
This study provides genetic instrumental evidence supporting a potential causal link between lifelong shorter telomere length and increased Alzheimer's disease risk, suggesting telomere biology may be directly involved in disease pathogenesis.
Limits
The genetic instrumental analysis relied on only three variants, which may not capture full biological variation in telomere regulation or may introduce horizontal pleiotropy. The cohorts were European/Danish, limiting generalizability to other ancestries, and the observed effect size was modest.
Cited by
- supports Mendelian randomization studies show that genetic propensity for longer telomeres directly predicts reduced risk of heart disease and dementia.