Assessing the Biological Mechanisms linking Smoking Behavior and Alzheimer’s Disease: Mediation Analysis of Metabolomic Data

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AbstractBackgroundSmoking is the most significant preventable health hazard in the modern world. It increases the risk of vascular problems, which are also risk factors for dementia. In addition, toxins in cigarettes increase oxidative stress and inflammation, which also have both been linked to the development of Alzheimer’s disease and related dementias (ADRD). However, the molecular mechanisms between smoking and ADRD are not well established. This study characterized these mechanisms using metabolomics data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodsBased on 1,266 people who enrolled in WRAP and had the necessary data to assess whether the smoking‐cognitive function relationship is mediated by CSF or plasma metabolites, we broke down our analyses into four steps, based on the product method (Figure 1). The associations between smoking status and cognitive functions, smoking and metabolites, and metabolites and cognitive functions were assessed. All models were adjusted for age, sex, race, education level, CES‐D score, body mass index, and weekly alcohol consumption. The outcomes were Preclinical Alzheimer Cognitive Composite III (PACC3) and composite scores for Immediate Learning, Delayed Recall, and Executive Function. Mediation analyses were then implemented, and the mediation effect of metabolites was computed to explore the role of metabolites in smoking‐cognitive function pathways. False discovery rate (<0.05) were applied as criteria for each step and 95% confidence intervals were used to verify the statistical significance for the metabolites that satisfied criteria.ResultsSix plasma metabolites were associated with smoking status and cognitive composite scores. Among them, N‐acetylneuraminate was significantly associated with PACC3 [95% confidence interval (CI): 0.00051‐0.01504] and Immediate Learning [95% CI: 0.00098‐0.01846] and was a significant mediator of the association between smoking status and these cognitive composites. The proportion of the total effect that was mediated by N‐acetylneuraminate was 12% for PACC3 and 13% for Immediate Learning.ConclusionsAs a mediator, N‐acetylneuraminate contributes to the association between smoking status and cognitive function. Interestingly, N‐Acetylneuraminate is a sialic acid and sialic acids have been found to be involved in several major changes associated with AD. For example, the CD33 sialic acid‐binding domain confers protection for late‐onset Alzheimer’s disease.