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

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 eIF4 G 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 eIF4 G 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.

Pharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: current review and perspectives

“…Human genetic backgrounds that show activating mutations in the mTOR signalling pathway are also significantly more likely to develop tau hyperphosphorylation and AD (H. Y. Cai et al, 2023). Similar to mTOR promoting Aβ oligomer formation, mTOR interacts with and integrates signalling pathways to propagate tau hyperphosphorylation and aberrant neurofilament formation (Extensively reviewed in (Mueed et al, 2018)).…”

“…Recent analyses on general population and AD patient GWAS data concerning (PI3K)/Akt/mTOR pathway proteins (Akt, S6K, eIF4E) suggest that genetic backgrounds with elevated mTOR-dependent response is causally linked to AD incidences (H. Y. Cai et al, 2023 ).…”

“…This reduction is linked to mTOR-mediated inhibition of key autophagy regulators, such as unc-51-like kinase 1 (ULK1) and transcription factor EB (TFEB) (H. Y. Cai et al, 2023 ). ULK1 is essential to autophagy initiation and autophagosome formation, and TFEB is a master regulator of lysosomal biogenesis.…”

“…Human genetic backgrounds that show activating mutations in the mTOR signalling pathway are also significantly more likely to develop tau hyperphosphorylation and AD (H. Y. Cai et al, 2023 ).…”

Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

“…Previous research employed genetic variants that modulate the expression of mTORC1's downstream targets regulating protein translation to study their effect on type 2 diabetes, rheumatic fever, Alzheimer's disease, Parkinson's disease, and cataract formation [32][33][34][35][36] . These studies utilised moderately associated (p-value < 5 × 10 -6…”