Cholesteryl ester transfer protein (CETP) polymorphism modifies the Alzheimer's disease risk associated with APOE ε4 allele

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.

The cholesteryl ester transfer protein (CETP) gene and the risk of Alzheimer’s disease

“…The CETP C-629A and TaqI B polymorphisms have been studied with respect to AD. A study in a Spanish population of the relationship between the CETP C-629A and I405V polymorphisms and the APOE*4 allele indicated that the CETP gene modifies AD risk possibly through modulation of brain cholesterol metabolism [17]. This modification effect was seen only for the C-629A polymorphism and not for the I405V.…”

“…While one previous study [17] showed evidence that the C-629A polymorphism of the CETP gene modifies the risk of AD in association with the APOE gene by reducing the risk of AD, another study found no effect of this gene on the disease [18]. We studied the I405V polymorphism of the CETP gene in relation to AD in a large population-based study and investigated whether this polymorphism is independently associated with AD, or acts in concert with the APOE gene in conferring risk for the disease.…”

Lipid Metabolism in Neurodegenerative Diseases

“…Furthermore, in fibroblasts from AD patients ACAT-1 mRNA levels are increased significantly. Recent genetic evidence associates a single nucleotide polymorphism (SNP, codon 405 isoleucine to valine (V405)) of the cholesterol ester transfer protein (CETP) with the lowered risk of dementia [65,66]. Similar to what was first noted by Alzheimer, ultrastructural studies on autopsied brain tissue from Alzheimer's disease patients using immunocytochemistry with an antibody that recognizes amyloid-beta peptides revealed cytosolic clusters of lipid droplets in immunopositive areas and there are cytosolic granules [67].…”

Cholesteryl ester transfer protein: The controversial relation to atherosclerosis and emerging new biological roles

“…APOE epsilon4 carriers that were homozygous for the CETP -629A allele had approximately a threefold lower risk of developing AD than the carriers of the -629C allele (69). These data suggest that CETP behaves as a modifier gene for AD risk associated with the APOE epsilon4 allele.…”

“…Ha and Barter (3) reported that CETP is present in fish, reptiles, birds, and mammals, but not in rats and mice. Chemical purification showed that CETP is a plasma glycoprotein consisting of 476 amino acids with an apparent molecular weight of [66][67][68][69][70][71][72][73][74]. This discovery led to subsequent cDNA cloning and tissue expression studies (5).…”