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

Area of Science:

• Genetics
• Neuroscience
• Aging Research

Background:

• A correlation exists between telomere length (TL) and Alzheimer's disease (AD), but underlying biological mechanisms are unclear.
• Investigating causal links and mediating factors is crucial for understanding AD pathogenesis.

Purpose of the Study:

• To explore the causal relationship between TL and AD using Mendelian randomization (MR).
• To evaluate the mediating role of brain imaging-derived phenotypes (IDPs) in the TL-AD association.
• To validate findings in independent cohorts.

Main Methods:

• Two-sample Mendelian randomization (MR) to assess causality between TL and AD.
• Two-step MR and multivariable MR to investigate mediation by nine brain IDPs.
• Independent cohort validation to confirm results.

Main Results:

• A longer genetically predicted TL was causally associated with a lower risk of AD (OR, 0.84; P=0.001).
• Nine brain IDPs were identified as partial mediators of the TL-AD association.
• The inverse association between TL and AD risk was attenuated after accounting for IDPs.

Conclusions:

• This study provides robust evidence for a causal link between longer TL and reduced AD risk.
• Brain IDPs partially mediate the protective effect of TL on AD, highlighting telomere biology's role.
• Findings support telomere maintenance as a potential therapeutic target for Alzheimer's disease.