Authors
Li Jiang, Xinyuan Chen, Jiangshun Qian, Kaiwen Fang, Chenyuan Dai, Dong Chang, Liang Jin, Wenjin Huang, Yuzheng Wang, Xiaomei Duan, Juan Wan, Mingqiang Li, Wendiao Zhang, Jinchen Li, Zijian Xiao, Heng Wu, Qingtuan Meng, Beisha Tang
Published in
Alzheimer's & dementia : the journal of the Alzheimer's Association. Volume 22. Issue 10. Pages e71845.
Abstract
Whether glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation lowers Alzheimer's disease (AD) risk via peripheral metabolic improvement or direct neuroprotection remains unclear.
Using blood and brain-cortex cis-acting expression quantitative trait loci (cis-eQTLs) for GLP-1R as instruments, we performed cis-Mendelian randomization (cis-MR) for AD and seven biomarkers. Mendelian randomization Bayesian model averaging (MR-BMA), cis-multivariable Mendelian randomization (cis-MVMR), and two-step cis-MR assessed 11 metabolic and inflammatory mediators, and tissue-specific cis-MVMR identified the causal tissue.
GLP-1R expression was associated with lower AD risk and cerebrospinal fluid phosphorylated tau (p-tau) levels. The cis-MVMR identified systolic blood pressure as the only independent mediator, whereas GLP-1R retained a direct protective effect on AD. Tissue-specific cis-MVMR attributed the effect predominantly to cortical (posterior inclusion probability [PIP] = 0.998) rather than blood GLP-1R expression (PIP = 0.002).
Genetic evidence supports GLP-1R as a potential target in AD, with a protective effect not fully explained by peripheral metabolic improvement and possibly involving cortical neuroprotection, supporting further investigation of brain-penetrant agents at preclinical or prodromal stages.
PMID:
42841315
Bibliographic data and abstract were imported from PubMed on 26 Oct 2026.
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