Nicotine Versus Non-Nicotine Constituents in Neurodegenerative Risk: Evidence from Multivariable Mendelian Randomization

Introduction: Nicotine has complex neuropharmacological actions through nicotinic acetylcholine receptors, but its independent role in neurodegenerative diseases remains unclear because tobacco smoke contains many non-nicotine toxicants. This uncertainty limits the interpretation of nicotine- and nAChR-targeted therapeutic strategies, especially as electronic nicotine delivery systems become more common. We used Mendelian randomization to genetically separate nicotine-related effects from smoking-related non-nicotine effects on major neurodegenerative diseases and related prodromal conditions. 

Methods: We performed univariable two-sample Mendelian randomization (MR) and multivariable MR (MVMR) analyses. Summary-level exposure data for cigarettes per day (CPD) and the nicotine metabolite ratio (NMR) were analyzed against individual-level, smoking-stratified outcome data derived from 337,334 UK Biobank participants, to evaluate their respective causal effects across six neurodegenerative outcomes: Alzheimer’s disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tremor, early cognitive impairment (EC), and other neurodegenerative diseases (OND). 

Results: MVMR analyses revealed that nicotine exposure was a causal risk factor for AD (ever smokers: OR=0.90, 95% CI 0.83-0.98; current smokers: OR=0.76, 95% CI 0.64-0.91). Nicotine exerted a causal protective effect against tremor (OR=1.24, 95% CI 1.03-1.49) and EC (OR=1.14, 95% CI 1.04-1.24) in current smokers. Non-nicotine tobacco constituents were identified as risk factors among former smokers for EC (OR=1.61, 95% CI 1.04-2.50). Discussion: Nicotine exhibits confirmed dual effects-protective for tremor/EC, but risky for AD/ALS. Its benefits may involve transient functional compensation via cholinergic/dopaminergic enhancement and synaptic plasticity, whereas risks may involve nAChR desensitization, calcium overload, and P38-MAPK tau phosphorylation. Non-nicotine constituents likely act through vascular and inflammatory injury, supporting smoking cessation. 

Conclusions: Exposure to nicotine can increase the risks of AD, while conferring protective effects against tremor and EC. Furthermore, exposure to non-nicotine tobacco constituents acts as a risk factor for the incidence of EC.