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Smoking promotes atherosclerosis and increases dementia risk, but nicotine exerts neuroprotective effect via \u03b17nAChR in preclinical studies. No studies explored the gene-gene, gene-environment interactions between<jats:italic>CHRNA7<\/jats:italic>polymorphism, apolipoprotein E (<jats:italic>APOE<\/jats:italic>) \u03b54 status and smoking on dementia risk. This case-control study recruited 254 late-onset Alzheimer\u2019s disease (LOAD) and 115 vascular dementia (VaD) cases (age \u226565) from the neurology clinics of three teaching hospitals in Taiwan during 2007\u20132010. Controls (N\u2009=\u2009435) were recruited from health checkup programs and volunteers during the same period. Nine<jats:italic>CHRNA7<\/jats:italic>haplotype-tagging single nucleotide polymorphisms representative for Taiwanese were genotyped. Among<jats:italic>APOE<\/jats:italic>\u03b54 non-carriers<jats:italic>, CHRNA7<\/jats:italic>rs7179008 variant carriers had significantly decreased LOAD risk after correction for multiple tests (GG + AG vs. AA: adjusted odds ratio\u2009=\u20090.29, 95% confidence interval\u2009=\u20090.13\u20130.64,<jats:italic>P<\/jats:italic>\u2009=\u20090.002). Similar findings were observed for carriers of GT haplotype in<jats:italic>CHRNA7<\/jats:italic>block4. A significant interaction was found between rs7179008, GT haplotype in block4 and<jats:italic>APOE<\/jats:italic>\u03b54 on LOAD risk. rs7179008 variant also reduced the detrimental effect of smoking on LOAD risk. No significant association was found between<jats:italic>CHRNA7<\/jats:italic>and VaD. 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