No 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, 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.

Alzheimer's disease (AD)—the most common type of dementia among the elderly—represents one of the most challenging and urgent medical mysteries affecting our aging population. Although dominant inherited mutation in genes involved in the amyloid metabolism can elicit familial AD, the overwhelming majority of AD cases, dubbed sporadic AD, do not display this Mendelian inheritance pattern. Apolipoprotein E (APOE), the main lipid carrier protein in the central nervous system, is the only gene that has been robustly and consistently associated with AD risk. The purpose of the current paper is thus to highlight the pleiotropic roles and the structure-function relationship of APOE to stimulate both the functional characterization and the identification of novel lipid homeostasis-related molecular targets involved in AD.