AbstractABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimer's disease (AD), independently or in concert with the APOE ε4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C−14T and C−477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C−14T polymorphism modified the risk of AD in an APOE ε4 allele‐dependent fashion: in APOE ε4 carriers, homozygous for the ABCA1 −14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 −14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (−14T) in concert with the APOE ε4 allele. © 2007 Wiley‐Liss, Inc.