Smoking and Dementia Status Among Older Americans: A Mendelian Randomization Analysis

Smoking is associated with dementia, but causality has not been well-established. Given smoking has a strong genetic component, we used genetic predisposition to smoking, based on a genome-wide association study (GWAS) from the GWAS & Sequencing Consortium of Alcohol and Nicotine use, as an instrumental variable. In a Mendelian randomization framework, we assessed the relationships between smoking and impaired cognitive status using the 2010 wave of the Health and Retirement Study. Cognitive status was assessed using cognition tests and categorized in three levels (normal cognition, cognitive impairment-non dementia, dementia). Smoking status was self-reported and classified into never, former, and current smoking. We used multivariable logistic regressions, Wald-type ratio estimators, and two-sample Mendelian randomization methods to examine associations and infer causal relationships. Among European genetic ancestry participants (n = 8741), current smoking was associated with cognitive impairment (OR = 1.62, 95%CI: 1.29, 2.01) relative to normal cognition. Two-sample Mendelian randomization results showed an inferred causal effect of smoking initiation on late-onset Alzheimer’s type dementia (MR-Egger: OR = 1.021, 95%CI: 1.017, 1.025). We observed no association between current smoking and dementia, or between former smoking and any cognitive status. No associations between smoking status and cognitive status were observed in the African genetic ancestry sample (n = 2501). Smoking behavior can give rise to cognitive impairment; therefore, promotion of smoking cessation is also important for brain health. Studies on dose and duration of smoking on cognition are critically needed, as well as continued research in non-European genetic ancestry study samples.