Polymorphism in the Cholesterol 24S-Hydroxylase Gene (CYP46A1) Associated with the APOEυ3 Allele Increases the Risk of Alzheimer’s Disease and of Mild Cognitive Impairment Progressing to Alzheimer’s Disease

Abstract

Background: Late-onset Alzheimer’s disease (LOAD) is associated with changes in certain proteins, such as ApoE and Cyp46A1, of the elimination route for cerebral cholesterol. The main lipoprotein involved in its transport is ApoE whose υ4 allele is the least efficient. However, the presence or absence of this allele does not determine the development of LOAD, which implies the existence of other susceptibility factors associated with the disease, such as the CYP46A1 gene that encodes the enzyme cholesterol 24S-hydroxylase. Objective: To find new data to contribute to the evaluation of whether the presence of the T allele in the polymorphic site rs754203 of the CYP46A1 gene leads to a greater risk of developing mild cognitive impairment (MCI) and LOAD. Furthermore, given the link between APOE and CYP46A1, we proceeded to relate both genotypes in each of the patient groups studied. Methods: We studied MCI and LOAD patients and also carried out an analysis of those MCI patients who progressed from a mild cognitive deterioration to a clinically evident Alzheimer’s disease during the study. Results: The frequency of the CYP46A1-T allele in the LOAD patients with APOEυ3 alleles is significantly higher with respect to the control group; the same occurs in the group made up of LOAD patients together with the MCI patients who progressed to LOAD. The risk of developing LOAD when this allelic combination exists is 2.262 times higher (95% CI 1.337–4.202). However, having the CYP46A1-T allele does not increase the risk of suffering from LOAD in carriers of the APOEυ4 allele, probably because the transport of cholesterol is already affected in such patients and possibly masks the effect of the CYP46A1-T allele. Conclusions: The CYP46A1-T allele increases the risk of suffering from LOAD in persons carrying the APOEυ3 allele.

Intron 2 (T/C) CYP46 Polymorphism Is Associated with Alzheimer’s Disease in Chinese Patients

“…Such a discrepancy is often found in case of selection bias and regional differences in the population structure. The genotype frequency distribution of our data set fell in the range [12,13,[22][23][24] , and represented a sample size similar to those of other studies. However, the inconsistence in association analyses between the current result and those in previous reports need further clarification.…”

The effects of cholesterol on learning and memory

“…In the periphery, systemic cholesterol is metabolized within the body to one of a number of products including the metabolite 27-hydroxycholesterol which can cross the BBB and enter the CNS (Heverin et al ., 2005). The role of cholesterol metabolites in learning and memory in humans have been explored by measuring levels of 24S- and 27-hydoxycholesterol in serum and the cerebrospinal fluid (Kolsch et al ., 2004; Papassotiropoulos et al ., 2002; van den Kommer et al ., 2009) and by identifying genetic polymorphisms related to cognitive impairment and Alzheimer’s disease (Fernandez del Pozo et al ., 2006; Fu et al ., 2009; Papassotiropoulos et al ., 2005). Animal studies of the effects of cholesterol metabolites on learning and memory have included knockout mice lacking 24-hydroxylase (Kotti et al ., 2006), infusion of 24-hydroxycholesterol into the brain (Zhao et al ., 2009) and manipulation of the CYP46A1 gene that encodes the enzyme cholesterol 24-hydroxylase (Hudry et al ., 2009).…”

“…Papassotiropoulos et al (2005) reported that a cluster of cholesterol-related genes including a single nucleotide polymorphism of CYP46A1 (rs754203) contributed to the risk for Alzheimer’s disease. Fernandez del Pozo and her colleagues examined the effect of the polymorphic site rs754203 on mild cognitive impairment and Alzheimer’s disease in patients with the ApoE3 or ApoE4 allele (Fernandez del Pozo et al ., 2006). They found that the polymorphism increased the risk of Alzheimer’s disease in those with the ApoE3 form but not in those with the ApoE4 form.…”

Polymorphism of CYP46A1 Gene and Alzheimer’s Disease in the Iranian Population

“…In studies of the relationship between CYP46A1 gene polymorphism and AD risk, a single nucleotide polymorphism (SNP) T/C in the region rs754203 of the CYP46A1 gene has been identified, and a significant correlation with an increased risk for AD has been revealed. According to these studies, the frequency of both the CYP46A1 TT-homozygotes genotype and the T allele was significantly higher in AD patients than in controls (15)(16)(17). Conversely, other studies reported that the CChomozygotes genotype was observed more frequently in AD patients than in the control subjects (18)(19)(20).…”