Genetic liability to opioid use disorder and dementia- related biological pathways: a Mendelian randomisation study

Journal article

Objectives
Opioid use disorder (OUD) is increasingly recognised as a risk factor for cognitive impairment and dementia, but the biological mechanisms underlying this association remain unclear. We aimed to investigate the involvement of established neurodegenerative, vascular, or inflammatory pathways.
Methods
We performed a two-sample Mendelian randomisation study using summary-level genetic data from nine genome-wide association studies of individuals predominantly of European ancestry. Genetic instruments for OUD liability were used to estimate associations with neurodegenerative, vascular, and inflammatory phenotypes, including amyloid-β, tau, cerebral amyloid angiopathy, cerebral microinfarcts, and C-reactive protein (CRP). Causal effects were estimated using inverse-variance weighted Mendelian randomisation, with replication and Bayesian colocalisation analyses used to further evaluate the findings.
Results
There was little evidence that genetic liability to OUD was associated with amyloid-β, tau, or vascular phenotypes. A modest positive association was observed with CRP (β=0.11, 95% CI 0.04–0.18, p=2×10^-3). This association was replicated in an independent dataset (β=0.12, 95% CI 0.05–0.19, p=1.59×10⁻³). A nominal inverse association was also observed with IL-15 (β = −0.23, 95% CI −0.43 to −0.03, p = 2.2×10⁻²), although colocalisation did not support a shared causal variant at implicated loci.
Conclusions
Genetic liability to OUD showed little evidence of association with the neurodegenerative or vascular phenotypes examined; however, these findings do not exclude the involvement of Alzheimer’s disease or cerebrovascular pathways, particularly given the limited power and the use of only three genetic instruments. The observed inflammatory associations should be considered hypothesis-generating, particularly given the lack of colocalisation support, and require further investigation.

Authors: Javidnia, S; Cronjé, HT; Karhunen, V; Gill, D; Bell, S

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: International Journal of Geriatric Psychiatry More from this journal
• Acceptance date: 2026-11-03
• EISSN: 1099-1166
• ISSN: 0885-6230
• Language: English
• Keywords: neurodegeneration; opioid use disorder; dementia; Mendelian randomisation; C-reactive protein; inflammation