Increased Brain β-Amyloid Load, Phosphorylated Tau, and Risk of Alzheimer Disease Associated With an Intronic CYP46 Polymorphism

Papassotiropoulos, Andreas; Streffer, Johannes; Tsolaki, Magda; Schmid, Simon; Thal, Dietmar Rudolf; Nicosia, Francesca; Iakovidou, Vassiliki; Maddalena, Alessia; Lütjohann, Dieter; Ghebremedhin, Estifanos; Hegi, Thomas; Pasch, Thomas; Träxler, Muriel; Brühl, Annette Beatrix; Benussi, Luisa; Binetti, Giuliano; Braak, Heiko; Nitsch, Roger M.; Höck, Christoph

doi:10.1001/archneur.60.1.29

Cited by 191 publications

(133 citation statements)

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“…However, these association studies have shown inconsistent results concerning variations in the CYP46A1 gene and the risk of AD (Desai et al, 2002;Helisalmi et al, 2006;Ingelsson et al, 2004;Papassotiropoulos et al, 2003). In addition a meta-analysis of the available data does not support a link between genetic variations in CYP46A1 and the risk of AD (Llorca et al, 2008).…”

Section: Introductionmentioning

confidence: 98%

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A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

et al. 2010

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Pages: 25 Pages including 2 tables Abstract:2 Variations in genes associated with cholesterol homeostasis have been reported to modify the risk of developing Alzheimer disease (AD). To date there have been few investigations into variations in genes directly involved in cholesterol biosynthesis and AD. We investigated the influence of the -911C>A polymorphism (rs3761740) in the hydroxy-methyl-glutaryl CoA reductase (HMGCR) gene promoter on basal and regulated transcription, plasma cholesterol levels and the association with AD. Under in vitro conditions the A allele was found to be significantly more responsive to SREBP-2 mediated regulation than the C allele. In an age and sex matched case-control study, the genotype distribution and allele frequency of this polymorphism were not associated with AD (OR=1.03; 95% CI=0.72-1.48). However, we did find evidence supporting an interaction between the HMGCR A allele, the APOE E4 allele and an altered risk of AD (OR=2.41; 95% CI=0.93-6.22).

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Section: Introductionmentioning

confidence: 98%

“…Intronic polymorphisms in CYP46A1 have been suggested to affect the load of both β-amyloid and phosphorylated tau protein in the brains of AD patients (Johansson et al, 2004;Papassotiropoulos et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

et al. 2010

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“…This "volume advantage" affords the individual greater physical resistance against neural degeneration. Thus, CYP46 T-alleles might mediate a risk for AD (Helisalmi et al, 2006;Papassotiropoulos et al, 2003). The suggestion of a protective role of the CYP46 Calleles (SNP rs754203) is supported by recent findings in a Chinese population.…”

Section: Discussionmentioning

confidence: 65%

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

Hänggi

Mondadori

Buchmann

et al. 2011

Neurobiology of Aging

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There is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain beta-amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46 TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TT-homozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between. Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TT-homozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences beta-amyloid metabolism. CYP46 C-carriers are privileged both in terms of beta-amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated. AbstractThere is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain -amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TThomozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between.Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TThomozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences -amyloid metabolism. CYP46 C-carriers are privileged both in terms of -amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated. Keywords:Cholesterol metabolism; Single nucleotide polymorphism; CYP46 (cholesterol 24S-hydroxylase); Parahippocampal and hippocampal morphology; Alzheim...

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“…In addition, previous studies showed that brain β-amyloid load and cerebrospinal fluid levels of phosphorylated tau protein in AD patients with the CYP46A1 gene TThomozygotes genotype were significantly higher than in subjects without the TT-homozygotes genotype. Therefore, polymorphism of the CYP46A1 gene may be involved in the pathogenesis of AD by regulating β-amyloid generation indirectly (14).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, polymorphism (T/C, rs754203) in the CYP46A1 gene is associated with an increased risk for AD along with increased beta-amyloid load in brain tissues and with increased cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau protein was reported (14). In studies of the relationship between CYP46A1 gene polymorphism and AD risk, a single nucleotide polymorphism (SNP) T/C in the region rs754203 of the CYP46A1 gene has been identified, and a significant correlation with an increased risk for AD has been revealed.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism of CYP46A1 Gene and Alzheimer’s Disease in the Iranian Population

et al. 2016

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Background: Cholesterol homeostasis in the brain has been demonstrated in the pathogenesis of Alzheimer's disease (AD). Experimental data support that brain cholesterol turnover can modulate central processes in AD pathogenesis. Excess cholesterol is eliminated from the brain via hydroxylation mediated by cholesterol 24S-hydroxylase (CYP46A1), a main mechanism of maintaining cholesterol homeostasis. The CYP46A1 gene has been suggested as a genetic risk factor for AD. Methods: In this case-control study, we analyzed an intronic CYP46A1 gene single-nucleotide polymorphism (SNP) in 100 AD patients and 80 age-and sex-matched control subjects in the Iranian population. Results: We found a significant difference in CYP46A1 TT-homozygotes genotype (χ 2 = 5.06, df =1, P = 0.02) and T allele frequency

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Increased Brain β-Amyloid Load, Phosphorylated Tau, and Risk of Alzheimer Disease Associated With an Intronic CYP46 Polymorphism

Abstract: CYP46 influences brain beta-amyloid load, cerebrospinal fluid levels of beta-amyloid peptides and phosphorylated tau, and the genetic risk of late-onset sporadic AD.

Cited by 191 publications

References 30 publications

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

A functional polymorphism in the HMGCR promoter affects transcriptional activity but not the risk for Alzheimer disease in Swedish populations

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

Polymorphism of CYP46A1 Gene and Alzheimer’s Disease in the Iranian Population

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