Investigating causal associations among inflammatory proteins, blood metabolites, and Alzheimer’s disease risk

Authors

• Shuai Liu, LSU Health Sciences Center - New OrleansFollow
• Jingjing Zhu, LSU Health Sciences Center - New OrleansFollow
• Hua Zhong, LSU Health Sciences Center - New OrleansFollow
• Dan Zhou, Zhejiang University, Hangzhou, China
• Quan Long, University of Calgary, Calgary, Canada
• Zichen Zhang, University of Texas MD Anderson Cancer Center, Houston, TX
• Xiaochen Yang, University of Pennsylvania, Philadelphia, PA
• Qing Wu, Ohio State University, Columbus, OH
• Chao Cheng, Baylor College of Medicine, Houston, TX
• Jianyong Wu, Ohio State University, Columbus, OH
• Hung N. Luu, Houston Methodist Research Institute, Houston, TX
• Jing Wang, Florida State University, Tallahassee, FL
• Bingxin Zhao, University of Hawaii at Manoa, Honolulu, HI
• Chong Wu, University of Texas MD Anderson Cancer Center, Houston, TX
• Youping Deng, University of Hawaii at Manoa, Honolulu, HI
• Lang Wu, LSU Health Sciences Center - New OrleansFollow

Document Type

Article

Publication Date

5-4-2026

Publication Title

BMC Psychiatry

Abstract

Alzheimer’s disease (AD) is a prevalent degenerative neurological disorder with limited treatment options. Prior studies reported specific metabolites and inflammatory proteins to be related to AD risk. However, the intricate relationship between inflammatory proteins, blood metabolites, and AD risk in European population remains unclear. Genetic instruments for 1,091 metabolites and 736 inflammatory proteins were derived from two recent comprehensive genome-wide association studies. Univariable Mendelian Randomization was employed to assess potential causal effects of metabolites on AD risk, potential effects of inflammatory proteins on metabolites, and effects of inflammatory proteins on AD risk. Multivariable MR (MVMR) was further applied to disentangle direct effects of proteins and metabolites on AD. Twelve metabolites were identified to be associated with AD risk, and 226 inflammatory proteins demonstrated likely to be causal effects on these 12 metabolites. Further examining the associations between such inflammatory proteins and AD risk revealed 22 associations for which the effect directions from inflammatory proteins to metabolites, from metabolites to AD risk, and from inflammatory proteins to AD risk were aligned, suggesting inflammatory protein - metabolite - AD risk pathway. MVMR further highlighted four trios in which the effect directions were consistent with the UVMR results, supporting a metabolite‑mediated pattern. This large‑scale genetic analysis highlights specific metabolites as direct contributors to AD risk and suggests that certain inflammatory proteins may influence AD primarily through downstream metabolic pathways. Our findings offer potential novel therapeutic targets for AD intervention.

PubMed ID

42082960

Volume

26

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.

Recommended Citation

Liu, Shuai; Zhu, Jingjing; Zhong, Hua; Zhou, Dan; Long, Quan; Zhang, Zichen; Yang, Xiaochen; Wu, Qing; Cheng, Chao; Wu, Jianyong; Luu, Hung N.; Wang, Jing; Zhao, Bingxin; Wu, Chong; Deng, Youping; and Wu, Lang, "Investigating causal associations among inflammatory proteins, blood metabolites, and Alzheimer’s disease risk" (2026). School of Graduate Studies Faculty Publications. 612.
https://digitalscholar.lsuhsc.edu/sogs_facpubs/612
10.1186/s12888-026-08136-4