Investigating the causal association between branched-chain amino acids and Alzheimer's disease: A bidirectional Mendelian randomized study

Xiao-Hang Qian; Xiao-Li Liu; Bin Zhang; Yuan Lin; Jian-Hua Xu; Gang-Yu Ding; Hui-Dong Tang

doi:10.3389/fnut.2023.1103303

Investigating the causal association between branched-chain amino acids and Alzheimer's disease: A bidirectional Mendelian randomized study

Front Nutr. 2023 Mar 31:10:1103303. doi: 10.3389/fnut.2023.1103303. eCollection 2023.

Authors

Xiao-Hang Qian^{1

2

3}, Xiao-Li Liu⁴, Bin Zhang⁴, Yuan Lin⁵, Jian-Hua Xu⁶, Gang-Yu Ding⁶, Hui-Dong Tang^{1

2

3}

Affiliations

¹ Department of Geriatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Department of Neurology, Shanghai University of Medicine and Health Sciences Affiliated Sixth People's Hospital South Campus, Shanghai, China.
⁵ Department of Gastroenterology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China.
⁶ Department of Neurology, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China.

Abstract

Background: There are many metabolic pathway abnormalities in Alzheimer's disease (AD). Several studies have linked branched-chain amino acid (BCAA) metabolism disorders with AD but have not obtained consistent results. The purpose of this study is to explore the causal association between BCAA concentration and the risk of AD.

Methods: A bidirectional Mendelian randomized (MR) study was applied to explore the causal effect between BCAA level and the risk of AD. Genetic instrumental variables from the genome-wide association study (GWAS) of serum BCAA levels [total BCAAs (115,047 participants), valine (115,048 participants), leucine (115,074 participants), and isoleucine (115,075 participants)] from the UK Biobank and AD (21,982 AD cases and 41,944 controls) from the International Genomics of Alzheimer's Project were applied to explore the causal effect through the inverse variance-weighted (IVW) method, MR-Egger, and weighted median, accompanied by multiple pluripotency and heterogeneity tests.

Results: The forward MR analysis showed that there was no causal effect of total BCAAs (OR: 1.067, 95% CI: 0.838-1.358; p = 0.838), valine (OR: 1.106, 95% CI: 0.917-1.333; p = 0.292), leucine (OR: 1.096, 95% CI: 0.861-1.396; p = 0.659), and isoleucine (OR: 1.457, 95% CI: 1.024-2.742; p = 0.037) levels on the risk of AD. The reverse analysis showed that AD was related to reduced levels of total BCAAs (OR: 0.979, 95% CI: 0.989-0.990; p < 0.001), valine (OR: 0.977, 95% CI: 0.963-0.991; p = 0.001), leucine (OR: 0.983, 95% CI: 0.973-0.994; p = 0.002), and isoleucine (OR: 0.982, 95% CI: 0.971-0.992; p = 0.001).

Conclusion: We provide robust evidence that AD was associated with a decreased level of BCAAs, which can serve as a marker for early diagnosis of AD.

Keywords: Alzheimer's disease; Mendelian randomized study; branched-chain amino acids; isoleucine; leucine; valine.

Grants and funding

This study was supported by the National Natural Science Foundation of China [81971014], the Hundred Faculty Talent Pool Program at Shanghai University of Medicine & Health Sciences in China, and the Shanghai Municipal Commission of Health and Family Planning [20184Y0056].