Recent studies indicate that there is a synergic association between butyrylcholinesterase-K variant (BChE-K) and apolipoproteinE-epsilon 4 (ApoE-epsilon 4) to promote risk for Alzheimer's disease (AD). Most subsequently replicative studies have been unable to confirm these finding. We attempted to replicate this finding in 105 AD cases and age and sex matched 129 controls from Tehran population, Iran. The BChE genotype of patients were found to be significantly different from controls (chi(2) = 12.2, d.f. = 2, p = 0.002). The frequency of BChE-K allele was also found to differ significantly in cases compared to controls [24% versus 12% (chi(2) = 20.6, d.f. = 2, p < 0.001)] leading to an increased risk of AD in subjects with this allele (OR = 2.5, 95% CI = 1.64-3.8, p = 0.001). This risk was found to increase from (OR = 2.37, 95% CI = 1.3-4.2, p = 0.006) in subjects less than 75 years old to (OR = 3.16, 95% CI = 1.41-7.1, p = 0.001) in subjects 75 years and older. But, the ApoE-epsilon 4 allele association risk was found to decrease from (OR = 9.5, 95% CI = 3.74-24.1, p = 0.001) in subjects <75 years to (OR = 1.36, 95% CI = 0.49-4.1, p = 0.58) in those subjects 75 years and older. Furthermore, we found a very strong synergic association between BChE-K and ApoE-epsilon 4 OR = 19.1 (95% CI = 428-85.45, p < 0.001). In spite of this, synergism decreased from OR = 36.2 (95% CI = 4.4-296, p = 0.001) in subjects <75 year olds to OR = 6.2 (95% CI = 0.9-72.4, p = 0.06) in subjects > or =75 years. We have found that BChE-K and ApoE-epsilon 4 alleles act synergistically to increase the risk of the late-onset AD, particularly in age group <75 years in Tehran, Iran.