Genetics
The CETP C-629A promoter variant modifies the Alzheimer's disease risk conferred by APOE epsilon4 (J Neurol 2006)
Original title: Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE epsilon4 allele
Since cholesterol regulates production of amyloid beta and CETP is central to regulating HDL levels that help clear excess cellular cholesterol, researchers studied whether two common CETP polymorphisms, promoter variant C-629A and exon 14 variant I405V, modify Alzheimer's disease susceptibility alone or together with APOE epsilon4, in 286 Spanish Alzheimer's disease patients and 315 healthy controls. Among APOE epsilon4 carriers, those homozygous for the CETP -629 A allele had an odds ratio of 2.33 (95% CI 1.01 to 5.37) for Alzheimer's disease, roughly three times lower than homozygous or heterozygous carriers of the CETP -629 C allele, who had an odds ratio of 7.12 (95% CI 4.51 to 11.24), with a highly significant interaction between APOE epsilon4 and the CETP -629 AA genotype (P less than 0.001). The authors conclude CETP acts as a modifier gene for the Alzheimer's disease risk conferred by APOE epsilon4, likely through effects on brain cholesterol metabolism.
Original abstract
Cholesterol regulates the production of amyloid beta (Abeta), which is central to the pathogenesis of Alzheimer's disease (AD), with high cellular cholesterol promoting and low cellular cholesterol reducing Abeta in vitro and in vivo. High density lipoprotein (HDL) plays a central role in the removal of excess cholesterol from cells, and cholesteryl ester transfer protein (CETP) is a crucial protein involved in the regulation of HDL levels. Two common polymorphisms in the promoter region (C-629A) and exon 14 I405V of the CETP gene are associated with CETP activity and HDL levels. To investigate if these sequence variants in CETP might be of importance in mediating susceptibility to AD, independently or in concert with apolipoprotein E (APOE) epsilon4 allele, we studied a sample of 286 Spanish AD patients and 315 healthy controls. In APOE epsilon4 carriers, homozygous for the CETP (-629) A allele had approximately a three times lower risk of developing AD (odds ratio 2.33, 95% CI 1.01-5.37), than homozygous and heterozygous carriers of the CETP (-629) C allele (odds ratio 7.12, 95% CI 4.51-11.24, P for APOE epsilon4/CETP (-629) AA genotype interaction < 0.001). Our data suggest that CETP behaves as a modifier gene of the AD risk associated with the APOE epsilon4 allele, possibly through modulation of brain cholesterol metabolism.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.