Causal Relationships Between Neuropathic Pain and Alzheimer’s Disease: A Multi-Omics Mendelian Randomization Study with Exploratory Evidence of a Potential Protective Role of Diabetic Neuropathy

Xiao Li,1,2,* Chi Zhang,1,2,* Di Liu,2 Hui Shang,1,3 Kejia Wang,2 Xianjian Lin,2 Junyi Zheng2 1The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Anesthesiology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3Shenzhen Hospital (Futian), Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junyi Zheng, Department of Anesthesiology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China, Email [email protected]: Neuropathic pain (NP) frequently co-occurs with Alzheimer’s disease (AD), yet the causal relationship and underlying molecular mechanisms between the two remain unclear, necessitating further investigation to elucidate their intrinsic connection.Methods: This study employed a bidirectional two-sample Mendelian randomisation (MR) approach to systematically analyse the association between six NP subtypes and AD. Concurrently, functional annotation and transcriptomic analysis were conducted using the GTEx v10 and GEO GSE156184 databases to explore potential molecular mechanisms.Results: The study revealed a significant inverse causal effect of diabetic neuropathy (DN) on AD risk (OR=0.86, 95% CI: 0.77~0.95, PIVW=0.0043), with sensitivity analyses confirming the robustness of this finding. Further analysis indicated that DN-associated SNPs regulate four tissue-specific genes including FAM200A and GPC2. These genes exhibit differential expression in the DN transcriptome and are significantly enriched in key pathways such as mitochondrial function and autophagy.Conclusion: This study provides the first evidence that DN may exert a protective effect against AD by regulating the aforementioned tissue-specific genes and associated pathways. This finding challenges the conventional understanding that chronic pain exacerbates AD and offers novel potential targets for developing therapeutic strategies. However, due to population limitations in the study, further experimental validation remains necessary.Keywords: neuropathic pain, Alzheimer disease, Mendelian randomization analysis, diabetic neuropathies, transcriptomics