Causal Association Between mTOR-Dependent Protein Levels and Alzheimer's Disease: A Mendelian Randomization Study
Hong-Yan Cai1,2, Si-Jia Hou3, Rui Wen1,2
1Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Taiyuan, Shanxi Province, China.
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.
Insights
This study investigated the mammalian target of rapamycin (mTOR) signaling in Alzheimer's disease (AD). Elevated AKT and RP-S6K levels may reduce AD risk, while increased eIF4E may elevate it, suggesting potential therapeutic targets.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The mammalian target of rapamycin (mTOR) pathway is implicated in Alzheimer's disease (AD) pathogenesis.
- Previous research suggests mTOR over-activation exacerbates AD development.
- Causal links between mTOR signaling proteins and AD risk remain unclear.
Purpose of the Study:
- To investigate the causal effects of mTOR signaling targets on Alzheimer's disease risk.
- To explore genetic associations between key mTOR pathway proteins and AD.
Main Methods:
- Utilized a two-sample Mendelian randomization analysis to assess causal relationships.
- Examined genetically predicted circulating levels of AKT, RP-S6K, EIF4E-BP, eIF4E, eIF4A, and eIF4G.
- Acquired summary data from genome-wide association studies (INTERVAL and International Genomics of Alzheimer's Project).
Main Results:
- Elevated AKT and RP-S6K levels were associated with a decreased risk of AD (OR=0.910, p=0.02).
- Increased eIF4E levels were associated with a genetically increased risk of AD (OR=1.805, p=0.045).
- No significant associations were found for EIF4-BP, eIF4A, or eIF4G with AD risk.
Conclusions:
- A causal relationship exists between mTOR signaling and AD risk.
- Activating AKT and RP-S6K, or inhibiting eIF4E, may offer potential therapeutic strategies for AD prevention and treatment.
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