A multi-omics insight into the sex-specific burden of tobacco-associated neurodegeneration: trends, projections, and mechanistic clues from the TH gene.

BACKGROUND: Tobacco exposure significantly influences neurological health, yet its specific associations with Parkinson's disease (PD) and Alzheimer's disease and other dementias (ADOD), including mechanisms, require clarification. METHODS AND MATERIALS: Using data from the Global Burden of Disease (GBD) 2021 study, multidimensional stratified comparisons of global PD and ADOD attributable to tobacco exposure were performed across dimensions including sex, socio-demographic index (SDI) quintiles, GBD sub-regions, and national levels. Furthermore, autoregressive integrated moving average and exponential smoothing models were incorporated to project trends until 2050. Bioinformatics analysis was conducted to identify key genes linking nicotine metabolism and sex differences. RESULTS: Tobacco exposure exerted a negative modulatory effect on PD burden but increased ADOD risk. Marked sex-specific differences existed, with males more affected. Regional heterogeneity was pronounced: PD impact was strongest in East Asia, while ADOD burden was highest in high-SDI regions. Projections showed rising ASRs for males but a decline for females. Mechanistically, the TH gene was a key nexus connecting PD, nicotine pathways, and sex differences, potentially explaining the stronger effect in males. CONCLUSIONS: Tobacco exposure differentially influences PD and ADOD, with distinct patterns by sex and region. It is detrimental for ADOD but may negatively modulate PD. The burden is projected to increase over the next three decades with persistent sex disparities. The TH gene may provides a mechanistic clue for the sex-heterogeneous effect against PD.