Polymorphism in the Cholesterol 24S-Hydroxylase Gene (CYP46A1) Associated with the APOE[epsilon]3 Allele Increases the Risk of Alzheimer's Disease and of Mild Cognitive Impairment Progressing to Alzheimer's Disease

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 ε4 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 APOEε3 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 APOEε4 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 APOEε3 allele. Copyright © 2006 S. Karger AG, Basel