Exploring the Causal Pathway From Telomere Length to Alzheimer’s Disease: An Update Mendelian Randomization Study

Abstract

Increasing evidence shows that telomere length shortening is associated with the risk for Alzheimer’s disease (AD), pointing to a potential modifiable target for prevention. However, the causality of this association is still not clear. To investigate the causal relationship between telomere length and AD, we use two-sample Mendelian randomization (MR) to assess potential causal inference. We used summary-level data for telomere length (9,190 participants) and AD (71,880 cases and 383,378 controls). We performed two-sample MR analysis with single nucleotide polymorphisms previously identified to be associated with telomere length. The MR analyses were conducted using the inverse-variance-weighted method and complemented with the maximum likelihood, weighted median, weighted mode approaches. MR evidence suggested that shorter telomere length was causally associated with a higher risk for AD (inverse-variance weighted estimate of odds ratio (OR): 1.03 per SD decrease of telomere length, P=1.21×10−2). The maximum likelihood, weighted median, weighted mode yielded a similar pattern of effects. The results were similar in sensitivity analyses. Using genetic instruments identified from large-scale genome-wide association study, robust evidence supports a causal role of telomere length shortening with increased risk of AD.

Editorial: Genetics of Age-Related Diseases and Their Risk and Protective Factors

“…Yu et al used summary-level data from GWAS to conduct a two-sample MR study demonstrating that shorter telomere length, a marker of biological aging, is causally associated with risk of AD. This strengthens previous findings on the topic (Zhan et al, 2015;Gao et al, 2019;Guo and Yu, 2019), extending the analyses to a larger sample size and using additional methods to test the robustness of the causal association.…”

Genetically predicted telomere length and its relationship with neurodegenerative diseases and life expectancy

“…Nevertheless, we observed evidence of directional pleiotropy and AD estimates were relatively inconsistent when using several MR methods. Interestingly, [40] reported a similar pattern of MR estimates when using summary-level data from [24] , where AD cases were both clinically diagnosed or AD-by-proxy (i.e., based on parental diagnoses). Despite the heritability of sporadic AD (∼80 %) [41] , and the proven value of proxy case-control association studies [42] , this could partially explain the decreased statistical power to detect consistent causal associations through robust MR methods.…”

Stress and telomere shortening: Insights from cellular mechanisms

“…Because these genetic variants are assigned randomly when passed from parents to offspring, this approach mimics a “naturally” randomized controlled trial and provides the strongest evidence of a causal relationship between the genotype (TL) and disease phenotypes without the influence of confounders that are unavoidable in observational studies. Mendelian randomization studies demonstrated that short TL based on the genetic score (what we call gTL) is associated with a wide variety of degenerative diseases (coronary heart disease, abdominal aortic aneurysm, IPF, and Alzheimer’s disease) and several autoimmune diseases (RA, celiac disease, type I diabetes and hypothyroidism) ( Zeng et al, 2020 ; Li et al, 2020 ; Telomeres Mendelian Randomization et al, 2017 ; Kuo et al, 2019 ; Duckworth et al, 2020 ; Scheller Madrid et al, 2020 ; Gao et al, 2019 ). However, long telomere length based on the genetic score is associated with many types of cancer and conditions of excess tissue growth (uterine fibroids, uterine polyps, and benign prostatic hyperplasia) ( Li et al, 2020 ; Zhang et al, 2020 ; Xu et al, 2020 ; Muskens et al, 2019 ; Gao et al, 2020 ).…”