Smoking Interacts With APOE ε4 to Influence Dementia: Evidence From the UK Biobank and Validation by Meta-Analysis of Longitudinal Studies.

BACKGROUND

Gene-by-environment interaction plays important roles in influencing dementia occurrence. Smoking is a well-established modifiable risk factor for all-cause dementia (ACD). However, its interaction effects with APOE ε4 as well as the underlying peripheral mechanisms are unclear.

METHODS

Panoramic smoking burden (PSB) and smoking history score (SHS) were constructed for 173,366 participants without dementia from the UK Biobank. The associations of PSB and SHS with ACD risk (median follow-up = 13 years) and their interactions with APOE ε4 carrier status were explored in death-competing risk models. Next, the interactions between smoking and APOE ε4 carrier status were validated by meta-analyzing epidemiological evidence searched up to May 2025. Finally, plasma proteomics, bioinformatics, and causal mediation analyses were conducted to reveal the potential mechanisms.

RESULTS

Smoking indices were associated with ACD risk, with significant multiplicative interactions of PSB (p < .001) and SHS (p = .031) by APOE ε4. The associations of smoking with ACD were more pronounced among ε4 noncarriers. Meta-regression of data from 207,887 participants validated that the relationship between smoking and ACD was modulated by APOE ε4 status (p = .011). Current smoking was associated with ACD risk exclusively among APOE ε4 noncarriers (p < .001). Inflammation, angiogenesis modulation, and regulation of endopeptidase activity could be mediating mechanisms.

CONCLUSIONS

These findings highlighted the interplay between smoking and APOE ε4 in influencing dementia, which should be considered in risk stratification and prediction models.