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.
Background: Paraoxonase 1 (PON1) functions to protect the cholinergic system against nerve gases and the organophosphate family of pesticides. Recent studies have shown that polymorphisms at the PON1 L55M and Q192R loci might affect individual susceptibility to experience-derived and environmental events such as the exposure to inhibitors of cholinesterase (ChEIs). Objective: ChEI therapy being the treatment of choice for mild-to-moderate Alzheimer’s disease (AD) patients, we determined whether genetic variations in the PON1 loci are associated with AD risk and whether they affect brain choline acetyltransferase (CHAT) activity, nicotinic receptor density, and β-amyloid (Aβ) levels in different regions of AD and age-matched control subjects. Methods: This pilot genetic study used a small cohort of brains from autopsy-confirmed AD patients and age-matched controls from the Douglas Hospital Brain Bank, Quebec, Canada. Results: The frequency of the M55M genotype at the PON1 L55M locus was found to be significantly increased in AD patients relative to age-matched controls (p < 0.05). Significant associations were observed between the PON1 L55M and Q192R polymorphisms and frontal cortex Aβ levels as well as CHAT activity and nicotinic receptor density in the temporal cortex. Conclusions: Our results suggest a prominent role for PON1 in the pathophysiology of common AD with a marked impact on the cholinergic system and Aβ levels in the brain.
Evidence suggests that the genes involved in brain lipid homeostasis are of particular relevance for Alzheimer's disease (AD) etiology. Among these genes, that encoding paraoxonase 1 (PON1) has gained newfound interest from a public health perspective, as recent studies have suggested that PON1 L55M and Q192R genetic variants might affect individual susceptibility to environmental events, such as exposure to cholinesterase inhibitors. Cholinesterase inhibitor therapy being the treatment of choice for patients with mild to moderate AD, we sought to answer two main questions: (i) are these genetic variants associated with increased AD risk, earlier age of onset/death, or shorter AD duration; and (ii) do they affect the neuropathological hallmarks of AD? This genetic study used a large cohort of clinical and autopsy-confirmed AD cases and age-matched, cognitively intact controls from the Douglas Hospital Brain Bank, Quebec, Canada (n = 1066). The evidence presented here suggests multiple gender-specific effects of PON1 polymorphisms on AD etiopathology. The L55M Met allele exerts an AD risk-enhancing effect only in men (P < 0.001), whereas both men and women carrying the M55M/Q192Q genotype exhibit increased survival (2.5 years, P < 0.05) and later age of onset (1.5 years, P < 0.05). These genetic variants are also individually and significantly associated, sometimes in opposite directions for both genders, with beta-amyloid levels (P < 0.001), senile plaque accumulation (P < 0.001) and choline acetyltransferase activity (P < 0.05) in, respectively, two of two, five of six, and three of six brain areas. These results suggest an involvement of the PON1 gene in AD etiopathology and responses to treatment.
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