title: Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer Disease: from risk factors to disease modulators.
abstract: Increasing biological and clinical findings argue for a link between brain cholesterol turnover and Alzheimer Disease (AD), high cerebral levels of the former increasing Abeta load. Cerebral cholesterol elimination involves two mechanisms dependent on Apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46). The aim of this study was to evaluate an intronic variation in CYP46 (intron 2, T --> C ) along with ApoE genotype as risk factors for AD and to establish the correlation between CYP46/ApoE polymorphism and disease progression. One-hundred and fifty-seven AD patients, who had been followed periodically through 1-year follow-up after enrollment, and 134 age- and gender-matched controls entered the study. The distribution of CYP46 genotypes was significantly different in AD compared to controls (P<0.004), being CYP*C allele higher in AD patients ( P<0.002). ApoE 4 genotype was more frequent in AD (41.4%) than in controls (15.9%, P<0.0001). The odds ratio (OR) for AD risk in CYP46*C carriers was 2.8, and in ApoE epsilon4 carriers was 4.05; the OR for having both CYP46*C and ApoE epsilon4 was 17.75, demonstrating the their synergic effect on AD risk. In AD patients, CYP46*C along with ApoE epsilon4 genotype were associated with a higher cognitive decline at 1-year follow-up (P<0.02). These findings provide direct evidence that CYP46 and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of cognitive decline.
authors.affiliation: Neurologic Clinic, University of Brescia, Spedali Civili de Brescia, Piazzale Spedali Civili 1, Brescia 25123, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.forename: Silvana
authors.initials: S
authors.lastname: Archetti
authors.forename: Chiara
authors.initials: C
authors.lastname: Agosti
authors.forename: Nabil
authors.initials: N
authors.lastname: Akkawi
authors.forename: Cristina
authors.initials: C
authors.lastname: Brambilla
authors.forename: Luigi
authors.initials: L
authors.lastname: Caimi
authors.forename: Carlo
authors.initials: C
authors.lastname: Caltagirone
authors.forename: Monica
authors.initials: M
authors.lastname: Di Luca
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padovani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics*; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D000072556:Cholesterol 24-Hydroxylase; D003545:Cysteine / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008609:Mental Status Schedule / Q000706:statistics & numerical data; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012307:Risk Factors; D013250:Steroid Hydroxylases / Q000235:genetics*; D013997:Time Factors; D014443:Tyrosine / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger; D014443:Tyrosine; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D003545:Cysteine