The role of the hippocampus and SLC39A8 in chronic musculoskeletal pain-induced dementia: a Mendelian randomization study

Despite observational studies suggesting a link between chronic musculoskeletal pain (CMP) and increased risk of cognitive decline and dementia, the causal nature of this relationship remains uncertain due to potential confounding factors and reverse causality. We employed two-sample Mendelian Randomization (TSMR), bidirectional MR, mediation MR, drug-target MR, and colocalization analysis, along with gene set enrichment and protein-protein interaction (PPI) analyses. TSMR assessed the causal associations between CMP and the risk of dementia and its subtypes, including Alzheimer's disease (AD), vascular dementia (VaD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and Parkinson's disease (PD). Bidirectional MR evaluated reverse causality, while mediation analyses identified potential mediators, focusing on neuroimaging and cognitive phenotypes. Drug-target MR investigated the role of the SLC39A8 gene, and colocalization analysis determined shared causal genetic variants. Gene set enrichment and PPI analyses elucidated the biological pathways implicated in the CMP-dementia relationship. Robust evidence established a causal relationship between chronic low back pain (LBP) and increased risk of PD, with knee osteoarthritis identified as a partial mediator, suggesting a pathway involving chronic inflammation. Bidirectional MR analysis revealed no evidence of reverse causality, further supporting the unidirectional causal link from LBP to PD. Colocalization analysis confirmed distinct genetic architectures for LBP and PD, while drug-target MR implicated the SLC39A8 gene as a potential mediator. Gene set enrichment and PPI analyses highlighted critical biological pathways, such as purine metabolism and glutamate receptor signaling. Suggestive evidence indicated potential causal links between limb pain and overall dementia, myalgia and VaD, as well as potential protective effects of Polymyalgia Rheumatica (PMR) against AD and rheumatism against PD. This study reveals a complex causal relationship between CMP and neurodegenerative diseases, particularly the robust link between LBP and PD. The findings underscore the need for further research to elucidate the underlying mechanisms and inform targeted prevention and treatment strategies.