Causal Association Between mTOR-Dependent Protein Levels and Alzheimer’s Disease: A Mendelian Randomization Study

Article type: Research Article

Authors: Cai, Hong-Yan^{a; b; 1} | Hou, Si-Jia^{c; 1} | Wen, Rui^{a; b} | Feng, Qi-Fan^{a; b} | Xi, Yu-Jia^{d; e} | Zhang, Sheng-Xiao^{d; e} | Qiao, Jun^{d; e} | Wu, Mei-Na^{a; *}

Affiliations: [a] Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China | [b] Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, Shanxi Province, China | [c] Department of Neurology, The First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China | [d] Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, China | [e] Shanxi Provincial Key Laboratory of Rheumatism Immune Microecology, Taiyuan, Shanxi Province, China

Correspondence: [*] Correspondence to: Mei-Na Wu, MD, PhD, Key Laboratory of Cellular Physiology at Shanxi Medical University, 56 Xinjian south Rd, Taiyuan 030002, China. Tel.: +86 13834678553; E-mail: wmna@163.com.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Most previous studies supported that the mammalian target of rapamycin (mTOR) is over-activated in Alzheimer’s disease (AD) and exacerbates the development of AD. It is unclear whether the causal associations between the mTOR signaling-related protein and the risk for AD exist. Objective:This study aims to investigate the causal effects of the mTOR signaling targets on AD. Methods:We explored whether the risk of AD varied with genetically predicted AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G circulating levels using a two-sample Mendelian randomization analysis. The summary data for targets of the mTOR signaling were acquired from published genome-wide association studies for the INTERVAL study. Genetic associations with AD were retrieved from the International Genomics of Alzheimer’s Project. We utilized the inverse variance weighted as the primary approach to calculate the effect estimates. Results:The elevated levels of AKT (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) and RP-S6K (OR = 0.910, 95% CI=0.840-0.986, p = 0.02) may decrease the AD risk. In contrast, the elevated eIF4E levels (OR = 1.805, 95% CI=1.002-1.174, p = 0.045) may genetically increase the AD risk. No statistical significance was identified for levels of EIF4-BP, eIF4A, and eIF4G with AD risk (p > 0.05). Conclusion:There was a causal relationship between the mTOR signaling and the risk for AD. Activating AKT and RP-S6K, or inhibiting eIF4E may be potentially beneficial to the prevention and treatment of AD.

Keywords: Alzheimer’s disease, causal relationships, mammalian target of rapamycin, Mendelian randomization

DOI: 10.3233/JAD-230128

Journal: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1477-1485, 2023