IBD and Cognitive Decline: A Systematic Review

August 18, 2026

Issue 16

Clinical Question

Is IBD associated with cognitive impairment and dementia, and do IBD therapies modify that risk?

Editor’s Bottom Line

These data provide another important reminder that uncontrolled gut inflammation may have serious systemic sequelae.

Reference

Motisi Bertulli A, Bezzio C, Marsano S, et al. Does inflammatory bowel disease play a role in cognitive decline? A systematic review. J Crohns Colitis. 2026;20(5):jjag057. https://doi.org/10.1093/ecco-jcc/jjag057

Synopsis

Emerging evidence links inflammatory bowel disease (IBD) to increased risks of cognitive impairment (CI) and dementia, yet the underlying mechanisms remain poorly characterized and study results have been conflicting.

This systematic review included 19 observational studies that assessed dementia risk in IBD patients. A quantitative synthesis was not performed due to heterogeneity in study design, cognitive assessment tools and outcome definitions. CI screening studies were considered complementary descriptive evidence only.

The authors reported that 13 studies found a significant positive association between IBD and CI and dementia. These included multiple large-scale cohort studies that demonstrated an elevated risk of all-cause dementia and Alzheimer’s disease (AD) in IBD patients. For example, one study reported a hazard ratio (HR) of 2.54 (95% confidence interval, 1.91–3.37) for dementia in IBD, with onset occurring on average seven years earlier than in matched controls.

Another reported HRs of 1.42 and 1.34 for CD and UC, respectively, and two recent meta-analyses reinforced a 22% increased risk of neurodegenerative disorders across nearly 1.6 million participants. Four studies found no significant relationship, with heterogeneity in comorbidity burden, environmental factors and study design contributing to discordant findings. Depression and systemic inflammation were independent contributors to CI in IBD patients in several analyses.

Among the seven studies that stratified patients by IBD therapy, all found lower odds of dementia in treated subgroups. Anti-tumor necrosis factor (TNF) therapy was consistently associated with reduced AD risk, with one study reporting adjusted odds ratios (aORs) of 0.37 for CD and 0.64 for UC with anti-TNF exposure. In contrast, thiopurine use was associated with a 29% reduction in AD risk and an 8.3% reduction per additional year of exposure. Another study found that after adjusting for biologic therapy, the association between IBD and neuroinflammatory outcomes largely disappeared.

Genetic analyses did not support a direct causal relationship between IBD and dementia. There were null findings across multiple analytic methods, though one set of investigators identified a significant association between genetically predicted UC and increased AD risk (OR 1.03, p=1.80×10⁻³). Additionally, the authors found shared genetic variants between IBD and neurodegenerative diseases, specifically in the HLA region associated with both CD and frontotemporal dementia, suggesting common inflammatory pathways that may contribute indirectly to neurodegeneration without implying direct causality.

Preclinical studies consistently demonstrated that induced colitis in mice produces neuroinflammation characterized by microglial activation, elevated brain cytokines (IL-1β, IL-6, TNF-α), blood–brain barrier disruption, and hippocampal-dependent memory impairment. In AD transgenic mouse models, colitis induction accelerated amyloid-β plaque deposition and impaired microglial phagocytosis. Immunomodulatory interventions including S100A9 inhibition and NLRP3 knockout mitigated neuroinflammatory markers and improved cognitive outcomes, suggesting a potential therapeutic role for immune-targeted agents in IBD-associated neurodegeneration.

Details

Study Design: Systematic review
Funding: No specific funding received
Allocation: Not applicable
Setting: Multicenter
Level of Evidence: Level 2a