title: Polymorphism in the cholesterol 24S-hydroxylase gene (CYP46A1) associated with the APOEpsilon3 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 Epsilon4 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 APOEpsilon3 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 APOEpsilon4 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 APOEpsilon3 allele.
authors.affiliation: Servicio de Neurología, Hospital Cruces, Barakaldo, Spain.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fernández Del Pozo
authors.forename: Maite
authors.initials: M
authors.lastname: Alvarez Alvarez
authors.forename: Manuel
authors.initials: M
authors.lastname: Fernández Martínez
authors.forename: Luis
authors.initials: L
authors.lastname: Galdós Alcelay
authors.forename: Fernando
authors.initials: F
authors.lastname: Gómez Busto
authors.forename: Jose A
authors.initials: JA
authors.lastname: Peña
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Alfonso-Sánchez
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Zarranz Imirizaldu
authors.forename: Marian M
authors.initials: MM
authors.lastname: de Pancorbo
mesh_terms: D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics*; D000072556:Cholesterol 24-Hydroxylase; D003072:Cognition Disorders / Q000175:diagnosis* / Q000453:epidemiology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase