The effects of nicotine on neurocognitive outcomes: evidence from a polygenic risk score analysis

IntroductionThe long-term nicotine effects on neurocognitive outcomes remain unclear. This knowledge gap is critical given rising nicotine product use in the UK, and the global dementia burden. Polygenic risk score (PRS) analyses allow us to explore the direct effects of nicotine on neurocognitive outcomes in a way that mitigates bias by confounding and reverse causation, which current research has not been able to achieve so far. We utilised PRSs for nicotine metabolite ratio (NMR) and cigarettes smoked per day (CPD) to investigate the direct effects of nicotine on a range of neurocognitive outcomes. MethodsUsing 334,757 participants from the UK Biobank cohort study, we tested whether an NMR PRS affects the risk of six major neurocognitive outcomes: all-cause dementia (ACD), Alzheimers disease (AD), all-cause Parkinsons disease (ACP), vascular dementia (VAD), total white matter hyperintensity volume (WMHv), and fluid intelligence score (FI). ResultsIncreased nicotine metabolism (indicating increased nicotine clearance from the body and therefore reduced nicotine exposure per cigarette smoked) was associated with decreased risk of AD in multivariable analyses with CPD adjusted for (OR = 0.95, 95% CI 0.91 to 1.00) (i.e. increased nicotine exposure increases AD risk). Additionally, smoking heaviness adversely affected WMHv in multivariable analyses adjusting for NMR ({beta} = 0.04, 95% CI -0.005 to 0.09). Our findings for nicotine and smoking heaviness in relation to our other neurocognitive outcomes indicate small effect sizes and confidence intervals cross the null. ConclusionOur findings demonstrate differential effects of nicotine on AD risk and smoking intensity on white matter integrity, requiring triangulation with complementary methodological approaches to better inform potential long-term risks of nicotine intake on neurocognitive outcomes.