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已发表论文
神经病理性疼痛与阿尔茨海默病之间的因果关系：一项多组学孟德尔随机化研究，探索性证据表明糖尿病神经病变可能具有潜在保护作用
Authors Li X, Zhang C, Liu D, Shang H, Wang K, Lin X, Zheng J
Received 17 July 2025
Accepted for publication 26 November 2025
Published 6 December 2025 Volume 2025:18 Pages 6527—6544
DOI https://doi.org/10.2147/JPR.S554433
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor King Hei Stanley Lam
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 work
Correspondence: Junyi Zheng, Department of Anesthesiology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China, Email dswzheng@163.com
Background: 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
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 work
Correspondence: Junyi Zheng, Department of Anesthesiology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China, Email dswzheng@163.com
Background: 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