Abnormal tau hyperphosphorylation is one of the central events in the development of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD), and phosphorylation of tau is accelerated by the increase in the level of neuronal cholesterol. Apolipoprotein E (APOE) promotes the neuronal uptake of cholesterol via APOE receptors such as the low-density lipoprotein receptor-related protein 1 (LRP1), and the APOE epsilon4 allele is associated with an increase in NFT burden in AD brain. In a case-control study in 246 AD patients and 237 healthy controls, we examined whether the combined gene effects between tau (intron 9, rs2471738) polymorphism and LRP1 (exon 3, rs1799986) polymorphism might be responsible for susceptibility to AD, independently or in concert with the APOE epsilon4 allele. Subjects carrying both the tau (intron 9, rs2471738) T allele (CT and TT genotypes) and the LRP1 (exon 3, rs1799986) T allele (CT and TT genotypes) had a 6 times higher risk of developing AD than subjects without these risk genotypes (odds ration = 6.20, 95% confidence interval = 1.74-22.05, p = 0.005), and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. These data suggest that the synergistic effects (epistasis) between tau and LRP1 might modify the risk of AD in an APOE epsilon4 allele-independent fashion.