HMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study.

TitleHMGCR is a genetic modifier for risk, age of onset and MCI conversion to Alzheimer's disease in a three cohorts study.
Publication TypeJournal Article
Year of Publication2015
AuthorsLeduc V, De Beaumont L, Théroux L, Dea D, Aisen P, Petersen RC, Dufour R, Poirier J
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative
JournalMol Psychiatry
Volume20
Issue7
Pagination867-73
Date Published2015 Jul
ISSN1476-5578
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.

DOI10.1038/mp.2014.81
Alternate JournalMol. Psychiatry
PubMed ID25023145
PubMed Central IDPMC4318698
Grant ListK01 AG030514 / AG / NIA NIH HHS / United States
P30AG010129 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
U19 AG010483 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
U24 AG21886 / AG / NIA NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada

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