Mendelian Randomization of Blood Metabolites Suggests Circulating Glutamine Protects Against Late-Onset Alzheimer’s Disease

Author:

Ramadan Ferris A.1,Arani Gayatri1,Jafri Ayan1,Thompson Tingting1,Bland Victoria L.2,Renquist Benjamin3,Raichlen David A.4,Alexander Gene E.56,Klimentidis Yann C.16

Affiliation:

1. Department of Epidemiology and Biostatistics, University of Arizona, Tucson, AZ, USA

2. Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA

3. School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA

4. Department of Biological Sciences and Anthropology, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, CA, USA

5. Department of Psychology, University of Arizona, Tucson, AZ, USA

6. BIO5 Institute, University of Arizona, Tucson, AZ, USA

Abstract

Background: Late-onset Alzheimer’s disease (LOAD) represents a growing health burden. Previous studies suggest that blood metabolite levels influence risk of LOAD. Objective: We used a genetics-based study design which may overcome limitations of other epidemiological studies to assess the influence of metabolite levels on LOAD risk. Methods: We applied Mendelian randomization (MR) to evaluate bi-directional causal effects using summary statistics from the largest genome-wide association studies (GWAS) of 249 blood metabolites (n = 115,082) and GWAS of LOAD (ncase = 21,982, ncontrol = 41,944). Results: MR analysis of metabolites as exposures revealed a negative association of genetically-predicted glutamine levels with LOAD (Odds Ratio (OR) = 0.83, 95% CI = 0.73, 0.92) that was consistent in multiple sensitivity analyses. We also identified a positive association of genetically-predicted free cholesterol levels in small LDL (OR = 1.79, 95% CI = 1.36, 2.22) on LOAD. Using genetically-predicted LOAD as the exposure, we identified associations with phospholipids to total lipids ratio in large LDL (OR = 0.96, 95% CI = 0.94, 0.98), but not with glutamine, suggesting that the relationship between glutamine and LOAD is unidirectional. Conclusions: Our findings support previous evidence that higher circulating levels of glutamine may be a target for protection against LOAD.

Publisher

IOS Press

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