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, 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.

Imaging Vascular Disease and Amyloid in the Aging Brain: Implications for Treatment

“…Both higher FCRP and higher Aβ burden were associated with less cortical thinning in subjects that were taking cholesterol-lowering drugs when compared with subjects who were not taking cholesterol drugs. This finding, which needs replication, is in line with other studies suggesting that statins confer some level of neuro-protection against late-life development of AD 39, 40 , see also 41 . Given that statin treatment has shown no reliable effect on clinical symptoms in subjects with dementia, it is more than plausible that statins only have an impact when started in midlife.…”

Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

“…Of note, Keller et al [51] recently highlighted an association between a polymorphism within the HMGCR promoter, rs3761740, and transcriptional activity by SREBP. Yet, we previously confirmed that this polymorphism was in linkage disequilibrium with rs3846662 (linkage disequilibrium 0.97) [32]. These two SNPs might thus act in concert to modulate HMGCR mRNA levels, at least in FH, in which the cholesterol metabolism is substantially deregulated.…”

“…), and epistasis between those genes may be responsible for the association between AA and suboptimal statin response in FH women. Evidence for epistasis for rs3846662 has previously been demonstrated: rs3846662 interacts with one locus in hepatic lipase (LIPC) to modulate HDL-C levels [49], and rs3846662 modulates Alzheimer's disease risk in women only [32], a finding suggesting an epistatic interaction between HMGCR and genotype defined by the X and Y chromosomes [50]. Of note, Keller et al [51] recently highlighted an association between a polymorphism within the HMGCR promoter, rs3761740, and transcriptional activity by SREBP.…”

“…The presence of the deletion of more than 15 kb of the promoter and first exon of the LDLR gene was assessed by Southern blotting as previously described [34] or by Sanger sequencing using standard laboratory procedures on a ABI 3130xl Sequencer (Applied Biosystems). Genotype profiling of rs3846662 of the HMGCR gene was performed with PCR followed by pyrosequencing as previously described [32]. APOE allele determination was also performed by PCR, followed by pyrosequencing using established protocols [35].…”

“…Notably, sex and apolipoprotein E (APOE) genotype have previously been shown to affect lipid traits [30] and response to statin treatment [31] in FH patients of French Canadian descent. Last year, in a population of elderly French Canadians not affected by FH, the effects of rs3846662 on cognitive impairment have also been shown to be modulated by sex and the presence of the APOE ε4 allele (APOE4) [32]. Our study thus sought to explore, in FH patients of French Canadian descent, the effects of rs3846662 and HMGCR alternative splicing on lipids levels and statin efficacy with respect to sex and APOE4 presence.…”