title: HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study.
abstract: Several retrospective epidemiological studies report that utilization of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitors called statins at mid-life can reduce the risk of developing sporadic Alzheimer's disease (AD) by as much as 70%. Conversely, the administration of these inhibitors in clinically diagnosed subjects with AD confers little or no benefits over time. Here, we investigated the association between AD and HMGCR rs3846662, a polymorphism known to be involved in the regulation of HMGCR exon 13 skipping, in a founder population and in two distinct mixed North American populations of converting mild cognitively impaired (MCI) subjects (Alzheimer's disease Cooperative study (ADCS) and Alzheimer's disease Neuroimaging Initiative (ADNI) cohorts). Targeting more specifically women, the G allele negative (G-) AD subjects exhibit delayed age of onset of AD (P=0.017) and significantly reduced risk of AD (OR: 0.521; P=0.0028), matching the effect size reported by the apolipoprotein E type 2 variant. Stratification for APOE4 in a large sample of MCI patients from the ADCS cohort revealed a significant protective effect of G negative carriers on AD conversion 3 years after MCI diagnosis (odds ratio (OR): 0.554; P=0.041). Conversion rate among APOE4 carriers with the HMGCR's G negative allele was markedly reduced (from 76% to 27%) to levels similar to APOE4 non-carriers (27.14%), which strongly indicate protection. Conversion data from the independent ADNI cohort also showed significantly reduced MCI or AD conversion among APOE4 carriers with the protective A allele (P=0.005). In conclusion, HMGCR rs3846662 acts as a potent genetic modifier for AD risk, age of onset and conversion.
authors.affiliation: 1] Centre for the Studies in the Prevention of Alzheimer's disease, Douglas Mental Health University Institute, Montreal, QC, Canada [2] Department of Nutrition, Institut de recherches cliniques de Montréal, Université de Montréal, Montreal, QC, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Leduc
authors.affiliation: Centre for the Studies in the Prevention of Alzheimer's disease, Douglas Mental Health University Institute, Montreal, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: De Beaumont
authors.affiliation: Centre for the Studies in the Prevention of Alzheimer's disease, Douglas Mental Health University Institute, Montreal, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Théroux
authors.affiliation: Centre for the Studies in the Prevention of Alzheimer's disease, Douglas Mental Health University Institute, Montreal, QC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Dea
authors.affiliation: Department of Neurosciences, University of California-San Diego, La Jolla, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Aisen
authors.affiliation: Alzheimer's Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Nutrition, Institut de recherches cliniques de Montréal, Université de Montréal, Montreal, QC, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Dufour
authors.affiliation: 1] Centre for the Studies in the Prevention of Alzheimer's disease, Douglas Mental Health University Institute, Montreal, QC, Canada [2] Derparment of Psychiatry, McGill University, Verdun, QC, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Poirier
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D053327:Apolipoprotein E4 / Q000235:genetics; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000503:physiopathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012737:Sex Factors
chemical_list: D053327:Apolipoprotein E4; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases