Unraveling the genetic underpinnings of mitochondrial traits and associated circulating inflammatory proteins in Alzheimer's disease: Mitochondrial HtrA2-T cell CD5 negative axis

Background Previous studies with limited sample sizes have indicated a link between mitochondrial traits, inflammatory proteins, and Alzheimer's disease. The exact causality and their mediation relationships remain unclear. Objective Our study aimed to delve into the genetic underpinnings of mitochondrial function and circulating inflammatory proteins in the pathogenesis of Alzheimer's disease. Methods We leveraged aggregated data from the largest genome-wide association study, including 69 mitochondrial traits, 91 circulating inflammatory proteins, and Alzheimer's disease. Bidirectional mendelian randomization (MR) analyses were performed to investigate their primary causal relationships. Thereafter a two-step MR mediation analysis was utilized to clarify the modulating effects of inflammatory proteins on mitochondria and Alzheimer's disease. Results Our study identified mitochondrial phenylalanine-tRNA ligase and 4-hydroxy-2-oxoglutarate aldolase as risk factors for Alzheimer's disease, and serine protease HtrA2 and carbonic anhydrase 5A as protective factors against Alzheimer's disease. Four inflammatory proteins (T-cell surface glycoprotein CD5, C-X-C motif chemokine 11, TGF-α, and TNF-related apoptosis-inducing ligand) played protective roles against Alzheimer's disease. Axin-1 and IL-6 increased the risk of Alzheimer's disease. Furthermore, T-cell surface glycoprotein CD5 was found to be a significant mediator between mitochondrial serine protease HTRA2 and Alzheimer's disease with the two-step MR method, accounting for 10.83% of the total effect. Conclusions Our study emphasized mitochondrial HtrA2-T cell CD5 as a negative axis in Alzheimer's disease, offering novel perspectives on its etiology, pathogenesis, and treatment.