Leukocyte Telomere Length Shortening and Alzheimer's Disease Etiology

Background: Several observational studies have found leukocyte telomere length (TL) to be associated with Alzheimer's diseases (AD) or dementia. However, these findings were based on small sample sizes and cannot clarify whether this relationship was causal. Genome-wide association studies (GWAS) have identified common variants associated with TL, providing a valuable resource for examining the causal effect of TL on AD using Mendelian Randomization (MR) methods. Objective: To examine if TL was causally associated with AD using GWAS summary statistics. Methods: Using a genetic risk score comprised of seven variants associated with leukocyte TL as an instrumental variable, we tested whether shorter TL was associated with a higher risk of AD by applying an MR approach to the summarized genome-wide association study data. Results: The genetic risk score for TL was associated with higher risk of AD [log-odds ratio (OR) = 0.003 for per TL-decreasing allele; 95% confidence interval (CI): 0.001, 0.005, p = 0.005]. Moreover, the MR analysis provided support for shorter TL to be causally associated with a higher risk of AD (log-OR = 0.04 per SD-decrease of TL; 95% CI: 0.01, 0.08, p = 0.01). Conclusion: We suggest that TL has a causal effect on the risk of AD.