Telomere Length, Brain Imaging-Derived Phenotypes, and Alzheimer's Disease: Mendelian Randomization Analysis

Previous studies have reported a correlation between telomere length (TL) and Alzheimer's disease (AD); however, the specific biological mechanisms supporting this association remain unclear. We used two-sample Mendelian randomization (MR) to systematically explore the putative causal relationships between TL, brain imaging-derived phenotypes (IDPs), and AD, while further evaluating the mediating role of IDPs using both two-step MR and multivariable MR. In addition, we utilized several independent validation cohorts to repeat the analysis, further strengthening our inferences. The MR analysis showed that a longer TL was causally associated with a lower risk for AD (OR, 0.84; 95% CI, 0.75 to 0.93; P = 0.001). In addition, the subsequent two-step MR results indicate that nine brain IDPs partially mediate the effect of TL on AD. The inverse association of genetically predicted TL with AD was attenuated after adjusting for these IDPs in multivariable MR. Our study provides further evidence for the causal relationship between TL and AD, with IDPs potentially partially mediating this association. Therefore, telomere biology may be a potential pathway involved in AD development, and identifying the important role of telomeres can draw more attention to the development of telomere-related diagnostics, treatments, and AD therapies.