A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia

Bullido, María J.; Artiga, María J.; Recuero, M.; Sastre, Isabel; García, Miguel Ángel; Aldudo, Jesús; Lendon, Corinne; Han, Sang Woo; Morris, John C.; Frank, A. Carolin; Vázquez, Jesús; Goate, Alison M.; Valdivieso, Fernando

doi:10.1038/ng0198-69

Cited by 272 publications

(192 citation statements)

References 18 publications

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“…It should be emphasised that no attempt to correct for multiple testing was made in other studies. 4,6,7 In order to circumvent the problem posed by correction for multiple testing (which could lead to false negative results), we then analysed the three promoter polymorphisms as a single haplotyped marker with three alleles. Thus the number of tests was reduced and the study had more power to detect a possible role of the APOE promoter.…”

Section: Discussionmentioning

confidence: 99%

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population

et al. 2000

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The apolipoprotein E (APOE, gene; apoE, protein) isoforms are associated with differential risk of Alzheimer's disease (AD). An additional involvement of APOE promoter polymorphisms in AD risk has recently been suggested by several studies. Indeed, three polymorphisms of the APOE regulatory region (-219 G/T, -427 C/T and -491 A/T) have been found associated with AD even after adjustment on the apoE status. We analysed these three promoter region polymorphisms in a large French case-control study (388 AD cases and 386 controls). We found that the -427 T and -491 A alleles were associated with an increased risk of developing AD, but not the -219 G/T alleles. However, a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles. We therefore retested association after adjustment on apoE status and found that the sole association which remained significant was the association with the -427 T allele. The α level was equal to 0.03 (0.09 after Bonferroni correction for multiple comparisons). Analysis of promoter haplotypes also yielded non-significant results. Thus our study does not reinforce the hypothesis of an independent involvement of the APOE promoter region polymorphisms in AD risk. European Journal of Human Genetics (2000) 8, 713-716.Keywords: Alzheimer's disease; APOE; promoter; linkage disequilibrium Since the initial report of an association between late-onset Alzheimer's disease (AD) and the apolipoprotein E (APOE, gene; apoE, protein) ε4 allele, 1 more than 100 association studies have established the involvement of APOE in AD. Carrying an ε4 allele increases the risk of AD in an allele dose manner: a meta-analysis found that the odds ratio (OR) is 3.2 (95% CI [2.8-3.8]) for individuals with one ε4 allele and 14.9 (95% CI [10.8-20.6]) for those homozygous for the ε4 allele. 2 The impact of the ε4 allele is present in early as well as in lateonset AD, but is highest between ages 60 and 80. 2,3 The presence of an APOE ε4 allele is neither sufficient nor essential for the development of AD. Other factors (genetic and/or environmental) should interact with the APOE genotype to determine the risk of AD. Recently it has been suggested that polymorphisms located in the regulatory region of the APOE gene could confer a risk of AD, even after adjustment on the apoE status. Three polymorphisms located respectively at -219 bp (Th1/E47cs), -427 bp and -491 bp of the transcriptional start site have been described. These biallelic polymorphisms are: -219 G/T, 4,5 -427 C/T 5,6 and 491 A/T 5-14 and the at-risk alleles for AD are -219 T, -427 C and -491 A. For two promoter polymorphisms (-427 and -491), allelic variants have been coupled with a reporter gene and transfected in astrocytic cells showing that haplotypes associated with the risk of AD are also associated with a higher transcription activity. 6 Therefore, an increase in expression of APOE could be the physiological mechanism responsible for the allelic association between the promot...

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Section: Discussionmentioning

confidence: 99%

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population

et al. 2000

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“…Multiple studies suggested that genetic variability in the regulatory region of APOE could modulate the risk associated with the APOEε4 isoform. In population-based studies, genetic association with AD, independent of APOEε4, was reported for three APOE promoter variations (-491A/T, -427T/C, and -219T/G) [124,125,126]. Functional analysis showed that these polymorphisms alter the transcriptional activity of the APOE promoter due to differential binding of transcription factors.…”

Section: Susceptibility Genes For Eoadmentioning

confidence: 99%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

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Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the ε4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE 4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies. KEYWORDS:Alzheimer dementia, neurodegeneration, mutations, linkage analysis, association analysis, mouse models DOMAINS: genetics (man), aging, neuroscience INTRODUCTIONAlzheimer's disease (AD) is a degenerative disorder of the central nervous system that causes progressive memory loss and cognitive decline during mid to late adult life, leading to dementia and ultimately death. AD is the most common form of dementia in the elderly, and represents the fourth largest cause of death in the developed world. In the near future, the impact of AD on our society will dramatically increase since, as populations live longer, the number of elderly people continues to grow.The clinical symptoms of AD display a substantial overlap with clinical symptoms observed in other neurodegenerative disorders with dementia as accompanying feature, such as *Corresponding author. Address: Department of Molecular Genetics (VIB8), Neurogenetics Group, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium; Tel: +32 3 8202601/Fax: +32 3 8202541 ©2003 with author.497 Rademakers et al.: Genetics of Early-Onset Alzheimer Dementia TheScientificWorldJOURNAL (2003) 3, 497-519 frontotemporal dementia (FTD) and Creutzfeldt Jacob's disease (CJD). Therefore a definite diagnosis of AD can only be obtained at autopsy. Extensive neuronal loss, and two particular brain lesions in the cerebral cortex, hippocampus, and amygdala characterize AD: the senile plaques (SPs) and neurofibrillary tangles (NFTs). The SPs are compact extracellular deposits that consist of a large amyloid β (Aβ) core surrounded by dystrophic neurites. NFTs are intraneuronal inclusions of paired helical filaments (PHF) that are mainly composed of hyperphosphorylated microtubule associated protein tau (MAPT).Based on the age at which the first clinical symptoms become...

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“…Since ibuprofen treatment reduced GFAP in our APP trangenics (Lim et al, 2000), we reasoned that control of inflammation and gliosis might reduce apoE production. Although some reports show an association between increased apoE mRNA (or promoter polymorphisms promoting such increases) and AD risk or amyloid plaques (Diedrich et al, 1991;Yamada et al, 1995;Bullido et al, 1998;Lambert et al, 1998;Laws et al, 1999), other reports show that this relation is restricted to apoE4 cases (Lambert et al, 1997;Roks et al, 1998;Song et al, 1998;Pahnke et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

Morita

Teter

Yang

et al. 2005

Neuropsychopharmacol

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Epidemiological and basic research suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) should protect against the most common forms of Alzheimer's disease (AD). Ibuprofen reduces amyloid (Ab) pathology in some transgenic models, but the precise mechanisms remain unclear. Although some reports show select NSAIDs inhibit amyloid production in vitro, the possibility that in vivo suppression of amyloid pathology occurs independent of Ab production has not been ruled out. We show that ibuprofen reduced Ab brain levels in rats from exogenously infused Ab in the absence of altered Ab production. To determine whether ibuprofen inhibits proamyloidogenic factors, APPsw (Tg2576) mice were treated with ibuprofen for 6 months, and expression levels of the Ab and inflammation-related molecules a 1 antichymotrypsin (ACT), apoE, BACE1, and peroxisome proliferator-activated receptor g) (PPARg) were measured. Among these, ACT, a factor whose overexpression accelerates amyloid pathology, was reduced by ibuprofen both in vivo and in vitro. IL-1b, which was reduced in our animals by ibuprofen, induced mouse ACT in vitro. While some NSAIDs may inhibit Ab42 production, these observations suggest that ibuprofen reduction of Ab pathology may not be mediated by altered Ab42 production. We present evidence supporting the hypothesis that ibuprofen-dependent amyloid reduction is mediated by inhibition of an alternate pathway (IL-1b and its downstream target ACT).

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A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia

Cited by 272 publications

References 18 publications

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population

Genetics of Early-Onset Alzheimer Dementia

Ibuprofen Suppresses Interleukin-1β Induction of Pro-Amyloidogenic α1-Antichymotrypsin to Ameliorate β-Amyloid (Aβ) Pathology in Alzheimer's Models

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