Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease

Wragg, Michelle; Talbot, Chris J.; Hutton, Mike; Goate, Alison M.

doi:10.1016/s0140-6736(96)91140-x

Cited by 228 publications

(133 citation statements)

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“…A genetic association between LOAD and a polymorphism in intron 8 of PSEN1 was reported with a twofold-increased risk for LOAD for the AA genotype [113]. This finding was replicated in some other LOAD populations [114,115,116], while others showed no association [117,118,119].…”

Section: Susceptibility Genes For Eoadmentioning

confidence: 83%

“…This study clearly illustrates the difficulties involved in association analysis as they are performed in several laboratories today. Studying the biological relevance of a genetic variation in a candidate gene will probably be indispensable to distinguish false positive findings from true risk factors for AD.In this view, the genes responsible for autosomal dominant EOAD, i.e., APP, PSEN, and APOE are interesting candidate genes that could harbor variations in their intronic and regulatory regions, responsible for susceptibility to EOAD in the general population.A genetic association between LOAD and a polymorphism in intron 8 of PSEN1 was reported with a twofold-increased risk for LOAD for the AA genotype [113]. This finding was replicated in some other LOAD populations [114,115,116], while others showed no association [117,118,119].…”

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confidence: 83%

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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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Section: Susceptibility Genes For Eoadmentioning

confidence: 83%

mentioning

confidence: 83%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

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“…Antibodies to PSI are reactive with plaques in all amyloid-13-related amyloidoses [21], whether or not they were linked to chromosome 14 and a recent report [15] indicates a genetic association between an intronic polymorphism in the PS1 gene and late-onset Alzheimer's disease. The converging mechanisms that lead different genotypes to similar Alzheimer's disease pathology may therefore all include presenilins in their pathway.…”

Section: Discussionmentioning

confidence: 96%

“…This view is also consistent with a recent report describing that an intron polymorphism in the PSI gene is related to approx. 20% of the cases of late-onset Alzheimer disease [15].…”

Section: Introductionmentioning

confidence: 99%

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

et al. 1996

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The majority of cases of early-onset familial Alzheimer disease are caused by mutations in the recently identified presenilin 1 (PS1) gene, located on chromosome 14. PS1, a 467 amino acid protein, is predicted to be an integral membrane protein containing seven putative transmembrane domains and a large hydrophilic loop between the sixth and seventh membranespanning domain. We produced 7 monoclonal antibodies that react with 3 non-overlapping epitopes on the N-terminal hydrophilic tail of PS1. The monoclonal antibodies can detect the full-size PS1 at Mr 47 000 and a more abundant Mr 28 000 product in membrane extracts from human brain and human cell lines. PC12 cells transiently transfected with PS1 constructs containing two different Alzheimer mutations fail to generate the 28 kDa degradation product in contrast to PC12 cells transfected with wild-type PS1. Our results indicate that missense mutations in this form of familial Alzheimer disease may act via a mechanism of impaired proteolytic processing of PS1.

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“…Several studies have reported that variation in the PSEN1promoter is associated with AD. However, most of the studies failed to show the relationship between its genotype and the risk of AD (3)(4)(5)(6)(7)(8)(9)(10). Furthermore, no haplotype analysis has been reported to date.…”

Section: Introductionmentioning

confidence: 99%

The -4,752 C/T Polymorphism in the Presenilin 1 Gene Increases the Risk of Alzheimer's Disease in Apolipoprotein E4 Carriers.

et al. 2002

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Objective Wesought to establish an association between sporadic Alzheimer' s disease (AD) and presenilin 1 (PSEN1) gene polymorphisms in the Japanese population. Methods A 5 kb fragment containing the putative promoter of the PSEN1gene for randomly selected control subjects wassubcloned into plasmid and sequenced to screen novel polymorphisms in this region. Patients and controls were genotyped for five polymorphic markers in the PSEN1 region. Wethen constructed haplotypes using the computer program HAPLO and compared the frequencies between cases and controls. Subjects A total of 189 AD cases (NINCDS-ADRDA criteria) and 240 controls were studied. Results Wediscovered a novel polymorphism with high heterozygosity on -4,752 of the PSEN1promoter region. A significant association was observed between the -4,752 C/T polymorphism and late-onset AD. The odds ratio for ADassociated with the CC vs non-CC genotype was 1.59 (95% CI=1.01-2.51), while that of £ 4 vs non-8 4 in APOE gene was ).The C allele was associated with a further increase in the risk ofAD in APOE8 4 carriers. We found 12 major haplotypes using five polymorphisms. The distribution pattern was significantly different between cases and controls.

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Genetic association between intronic polymorphism in presenilin-1 gene and late-onset Alzheimer's disease

Cited by 228 publications

References 11 publications

Genetics of Early-Onset Alzheimer Dementia

Genetics of Early-Onset Alzheimer Dementia

Characterization of human presenilin 1 using N‐terminal specific monoclonal antibodies: Evidence that Alzheimer mutations affect proteolytic processing

The -4,752 C/T Polymorphism in the Presenilin 1 Gene Increases the Risk of Alzheimer's Disease in Apolipoprotein E4 Carriers.

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