Opioid use disorder and dementia risk: evidence from observational and genetic analyses in diverse ancestry cohorts.
Javidnia S., Roe JM., Karhunen V., Gill D., Bell S., Deak JD., Levey D., Kember RL., Kranzler HR., Cronjé HT., Burgess S., Gelernter J., Ebmeier KP., Topiwala A.
INTRODUCTION: Opioid use disorder (OUD) may adversely affect brain health, but its role in dementia risk remains poorly understood. METHODS: We investigated associations between OUD and dementia using observational data from 222,518 participants (European and African ancestry) in the Million Veteran Program and Mendelian randomization (MR) using genome-wide association study summary statistics from 6,066,918 individuals. Polygenic risk score (PRS) analyses were conducted in 229 opioid-naïve Lifebrain consortium participants with longitudinal magnetic resonance imaging data. RESULTS: OUD was associated with increased risk of all-cause dementia (hazard ratio = 1.56, 95% confidence interval [CI]: 1.39 to 1.76), Alzheimer's disease, and vascular dementia. MR supported a potential causal link between genetic liability to OUD and dementia (inverse variance weighted odds ratio = 1.77, 95% CI: 1.43 to 2.19). Genetic variation in the μ-opioid receptor gene was also associated with dementia risk. No PRS associations were found with brain structure. DISCUSSION: These findings suggest a potential causal role for OUD in dementia, implicating μ-opioid receptor pathways in neurodegeneration.