Involvement of ApoE E4 and H63D in Sporadic Alzheimer's Disease in a Folate-Supplemented Ontario Population

Percy, Maire E.; Moalem, Sharon; García, Ángeles; Somerville, Martin J.; Hicks, Matt; Andrews, D. F.; Azad, Azar; Schwarz, Peter; Zavareh, Reza Beheshti; Birkan, Rivka; Choo, C M; Chow, Vinca; Dhaliwal, Sandeep; Duda, Victoria; Kupferschmidt, Anthony L.; Lam, Kwok W.; Lightman, Deborah; Machalek, Karolina; Mar, Wanna; Nguyen, Frank; Rytwinski, Piotr J.; Svara, Erin; Tran, Maithy; Yeung, Lisa; Zanibbi, Katherine; Zener, Rebecca; Ziraldo, Melissa; Freedman, Morris

doi:10.3233/jad-2008-14107

Cited by 32 publications

(27 citation statements)

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“…We did not replicate the previous finding of an effect of HFE SNPs on risk of AD and an epistatic interaction for risk with APOE ε4 genotype, but we cannot yet rule out an association of HFE SNPs with AD age of onset or phenotypic interactions [25,27,28].…”

Section: Discussioncontrasting

confidence: 99%

“…The discovery GWAS meta-analysis datasets used in the study contain large sample sizes (in total 54,162 for AD and 23,986 for serum iron status) and show both AD and serum iron measures to have a strong polygenic components [27,31]. For serum iron measures using replication cohorts, the lead SNPs at the 11 significant loci explained 3.4, 7.2, 6.7, and 0.9% of the phenotypic variance for iron, transferrin, saturation, and (log-transformed) ferritin, respectively [30].…”

Section: Gps Analysismentioning

confidence: 99%

“…Several studies previously reported an increased frequency of the HFE H63D (rs1799945) mutation in AD patients [25], but these findings have not been replicated in the largest AD GWAS meta-analysis [26]. There is evidence of interaction effects, which would not be apparent in GWAS meta-analyses, involving H63D and APOE ε4 alleles where the combination appears to affect age of onset and, to a lesser extent, risk [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

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No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

Lupton

Benyamin

Proitsi

et al. 2017

JAD

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Abstract. Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control 1 Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer's disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided data but did not participate in analysis or writing of this report (except those who are named authors). Membership of the GERAD1 Consortium is provided in the Acknowledgments section.2 Data used in preparing this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators may be found at: http://adni.loni.usc.edu/wpcontent/uploads/how to apply/ADNI Acknowledgement List.pdf * Correspondence to: Michelle K. Lupton, PhD, QIMR

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Section: Discussioncontrasting

confidence: 99%

Section: Gps Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

Lupton

Benyamin

Proitsi

et al. 2017

JAD

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“…Previous studies report different effects in male and female patients such that in females APOE ε 4 was associated with AD in HFE D63 carriers, whereas in males the APOE ε 4 allele predisposed to AD in noncarriers of HFE D63 (Percy et al, 2008).…”

Section: Discussionmentioning

confidence: 97%

HFEH63D, C282Y andAGTR1A1166C Polymorphisms and Brain White Matter Lesions in the Aging Brain

Gebril

Kirby

Brayne

et al. 2011

Journal of Neurogenetics

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Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens' scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.

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“…There is also evidence that, compared with age-and sex-matched controls, AD patients carrying both the APOE ε4 allele and the H63D polymorphism of the hemochromatosis protein-related class Ilike major histocompatibility gene HFE are significantly more susceptible to earlier development of AD than those carrying only one of these mutations [57]; reviewed by [58]. More recently, researchers have detected the rs75932628 singlenucleotide polymorphism (SNP) within the triggering receptor expressed on myeloid cells 2 (TREM2) gene, leading to an R47H substitution, which increases the risk of developing AD in carriers by virtually the same magnitude as the presence of one APOE ε4 allele [59]; reviewed by [60].…”

Section: Introductionmentioning

confidence: 99%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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Involvement of ApoE E4 and H63D in Sporadic Alzheimer's Disease in a Folate-Supplemented Ontario Population

Cited by 32 publications

References 0 publications

No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease

HFEH63D, C282Y andAGTR1A1166C Polymorphisms and Brain White Matter Lesions in the Aging Brain

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

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