Causal association between constipation and dementia and the role of the gut microbiota: A two-sample Mendelian randomization analysis

JOURNAL/agad/04.03/02274129-202604000-00002/figure1/v/2026-04-25T073659Z/r/image-tiff Objectives: Constipation is highly prevalent in the elderly population, while dementia imposes a severe global health burden associated with aging. Observational studies suggest a link between constipation and cognitive decline, but confounding factors and reverse causality hinder causal inference. This two-sample Mendelian randomization (MR) study aimed to investigate the potential causal relationship between constipation and various dementia subtypes and to explore the mediating role of the gut microbiota. Methods: We utilized summary-level data from large-scale, European-ancestry Genome-Wide Association Studies (GWAS). Genetic instruments for constipation were selected from the GWAS Catalog ( P < 5 × 10⁻⁶). data for Alzheimer’s disease and seven other dementia subtypes (e.g., vascular dementia and Lewy body dementia) were sourced from FinnGen and the IEU GWAS database. The gut microbiota data were obtained from the Dutch Microbiome Project. The primary analysis employed the inverse-variance weighted (IVW) method, supplemented by weighted median and MR‒Egger regression. Sensitivity analyses included Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis to assess pleiotropy, heterogeneity, and robustness. Results: Genetically predicted constipation was significantly associated with an increased risk of Alzheimer’s disease (IVW odds ratio (OR) = 1.15; 95% CI: 1.02 to 1.30, P = 0.0260). Consistent estimates were obtained using weighted median (OR = 1.22, 95% CI: 1.05 to 1.43, P = 0.0103) and MR‒Egger bootstrap methods (OR = 1.31, 95% CI: 1.05 to 1.65, P = 0.005). Sensitivity analyses supported the robustness of this association and indicated a unidirectional causal effect from constipation to Alzheimer’s disease. However, no significant causal links were found between constipation and the other dementia subtypes (all P > 0.05). While MR identified causal relationships between constipation and seven microbial taxa and between thirteen microbial taxa and Alzheimer’s disease, no overlapping microbiota were found, suggesting that the gut microbiota may not mediate the link between constipation and Alzheimer’s disease. Conclusions: This MR study provides evidence supporting a potential causal role of constipation in increasing the risk of Alzheimer’s disease, but not other major dementia subtypes, in populations of European ancestry. The mechanism appears to be independent of the specific gut microbial pathways tested here, implicating alternative pathways such as systemic inflammation or vascular dysfunction. These findings highlight constipation as a potential modifiable risk factor for aging-related cognitive decline, warranting further investigation into its pathophysiology and preventative implications for Alzheimer’s disease.