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Mol Psychiatry. 2015 Jul;20(7):867-73. doi: 10.1038/mp.2014.81. Epub 2014 Jul 15.

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

Author information

1
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.
2
Centre for the Studies in the Prevention of Alzheimer's disease, Douglas Mental Health University Institute, Montreal, QC, Canada.
3
Department of Neurosciences, University of California-San Diego, La Jolla, CA, USA.
4
Alzheimer's Disease Research Center, Mayo Clinic College of Medicine, Rochester, MN, USA.
5
Department of Nutrition, Institut de recherches cliniques de Montréal, Université de Montréal, Montreal, QC, Canada.
6
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.

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.

PMID:
25023145
PMCID:
PMC4318698
DOI:
10.1038/mp.2014.81
[Indexed for MEDLINE]
Free PMC Article

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