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

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, 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 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 [ADCS and 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 [O.R.: 0.521; P = 0.0028], matching the effect size reported by the APOE2 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 three years after MCI diagnosis [O.R.: 0.554; P = 0.041]. Conversion rate among APOE4 carriers with the HMGCR’s G negative allele was markedly reduced [from 76% to 26.97%] 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 act as potent genetic modifier for AD risk, age of onset and conversion.