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.

Figure 1. Age of onset in HMGCR rs3846662 intron 13 G negative vs G positive carriers

The joint table contrasts the effects of the different genetic variants of the HMGCR gene to those of APOE using a Wilcoxon chi-square rank test. N: sample size; X²= chi square; r: correlation; HMGCR G-: G negative genotype versus G positive. Asterisks represent significant association for AD at the 95% C.I. (*) or 99% C.I. (**) level.

Figure 2. Kaplan–Meier Estimates of the Rate of Progression from Normal to Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD)

Conversion rate, stratified by APOE genotype, among subjects from the ADNI cohort as a function of the HMGCR intron13 genotype (APOE4 positive subject, P = 0.005). AA: G negative genotype; AG/GG: G positive genotype.