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

Article type: Research Article

Authors: Ramadan, Ferris A.^{a; *} | Arani, Gayatri^a | Jafri, Ayan^a | Thompson, Tingting^a | Bland, Victoria L.^b | Renquist, Benjamin^c | Raichlen, David A.^d | Alexander, Gene E.^{e; f} | Klimentidis, Yann C.^{a; f; *}

Affiliations: [a] Department of Epidemiology and Biostatistics, University of Arizona, Tucson, AZ, USA | [b] Department of Nutritional Sciences, University of Arizona, Tucson, AZ, USA | [c] School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, USA | [d] Department of Biological Sciences and Anthropology, Human and Evolutionary Biology Section, University of Southern California, Los Angeles, CA, USA | [e] Department of Psychology, University of Arizona, Tucson, AZ, USA | [f] BIO5 Institute, University of Arizona, Tucson, AZ, USA

Correspondence: [*] Correspondence to: Ferris A. Ramadan and Yann C. Klimentidis, Department of Epidemiology and Biostatistics, University of Arizona, 1295 North Martin Avenue, Tucson, AZ 85724, USA. E-mails: [email protected]; [email protected].

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.

Keywords: Alzheimer’s disease, glutamine, Mendelian randomization, metabolites

DOI: 10.3233/JAD-231063

Journal: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 1069-1078, 2024