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Background: The rs405509 polymorphism ofthe apolipoprotein E (APOE) promoter is related to Alzheimer’sdisease (AD). The T/T allele of rs405509 is known to decrease the transcription of the APOE gene and lead to impairments in specific brain structural networks with aging; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects brain functional connectivity (FC) in aging.Methods: We investigated the effect of the rs405509 genotype (T/T vs. G-allele) on age-related brain FC using functional magnetic resonance imaging. Forty-five elderly TT carriers and 45 elderly G-allele carriers were scanned during a working memory (WM) task.Results: We found that TT carriers showed an accelerated age-related increase in functional activation in the left postcentral gyrus compared with G-allele carriers. Furthermore, the FC between the left postcentral gyrus and some key regions during WM performance, including the right caudal and superior frontal sulcus (SFS), was differentially modulated by age across rs405509 genotype groups.Conclusions: These results demonstrate that the rs405509 T/T allele of APOE causes an age-related brain functional decline in nondemented elderly people, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis.

Background : The rs405509 polymorphism ofthe apolipoprotein E (APOE) promoter is related to Alzheimer'sdisease (AD). The T/T allele of rs405509 is known to decrease the transcription of the APOE gene and lead to impairments in specific brain structural networks with aging; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects brain functional connectivity (FC) in aging. Methods : We investigated the effect of the rs405509 genotype (T/T vs. G-allele) on age-related brain FC using functional magnetic resonance imaging. Forty-five elderly TT carriers and 45 elderly G-allele carriers were scanned during a working memory (WM) task. Results : We found that TT carriers showed an accelerated age-related increase in functional activation in the left postcentral gyrus compared with G-allele carriers. Furthermore, the FC between the left postcentral gyrus and some key regions during WM performance, including the right caudal and superior frontal sulcus (SFS), was differentially modulated by age across rs405509 genotype groups. Conclusions : These results demonstrate that the rs405509 T/T allele of APOE causes an age-related brain functional decline in nondemented elderly people, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis. [ABSTRACT FROM AUTHOR]

Highlights • The relationship between APOE - 491 A/T, -427C/T, and −219 T/G SNP and AD was studied. • The −491 T allele and the −491 A/T genotype protect against AD. • The −219 T/G heterozygosity is a potential risk factor of AD. Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a complex aetiology. The ε4 allel of the apolipoprotein E gene (APOE) is the only confirmed genetic risk factor for the development of AD. In addition, polymorphisms at the promoter region of the APOE gene are assumed to modulate the susceptibility to AD by their different affinity to the transcription factors thus affecting the expression of the gene. In the presented study, we investigated the association between −491 A/T (rs449647), −427C/T, (rs769446) and −219 T/G (rs405509) single nucleotide polymorphisms (SNPs) of APOE gene and AD risk in the Polish population. We found that only the −491 T allele and −491 A/T genotype acted as protective factors against AD, whereas the −219 T/G heterozygosity increased risk for AD in APOE ε4 carriers but not in APOE ε4 non-carriers. What is more, haplotype frequency estimation showed significant positive for A-T-T-C-C and A-T-G-C-C haplotypes or negative for A-T-T-T-C and T-T-T-T-C haplotypes associations with AD. These results contribute to the evidence that APOE promoter polymorphisms modulate risk for AD. [ABSTRACT FROM AUTHOR]

Polymorphisms of the apolipoprotein E (APOE) promoter rs405509 are related to Alzheimer's disease (AD). The T/T allele of rs405509 decreases the transcription of the APOE gene and leads to impairments in a specific brain structural network in aged individuals; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects white matter networks during aging. Here, we investigated the effect of the rs405509 genotype (T/T versus G-allele) on age-related brain white matter structural networks via construction of the graph theory-based structural connectome using diffusion MRI data in a large cohort. Network communication efficiency was quantified, along with the network's betweenness centrality (Bc), global efficiency, local efficiency, and shortest path length. Regarding cognition, TT carriers had significant negative correlations between age and memory performance and between age and executive functions. A network analysis showed that TT carriers had an accelerated age-related loss of Bc and that regional Bc decreased in the left inferior frontal gyrus pars opercularis, the left posterior cingulate cortex, the right inferior occipital gyrus (IOG.R), and the left angular gyrus (ANG.L). Additional brain-behavior relationship analyses showed that polymorphism of rs405509 and age have strong interaction effects on the association of nodal Bc and cognition, mainly in the IOG.R and ANG.L. These results demonstrate that the rs405509 T/T allele of APOE causes an age-related cognitive decline in non-demented elderly people, possibly by modulating brain network communication efficiency, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis. [ABSTRACT FROM AUTHOR]

The polymorphism of the Apolipoprotein E (APOE) promoter rs405509 can regulate the transcriptional activity of the APOE gene and is related to Alzheimer's disease (AD). However, its effects on cognitive performance and the underlying brain mechanisms remain unknown. Here, we performed a battery of neuropsychological tests in a large sample (837 subjects) of nondemented elderly Chinese people, and explored the related brain mechanisms via the construction of diffusion MRI-based structural connectome and graph analysis from a subset (84 subjects) of the sample. Cognitively, the rs405509 risk allele (TT) carriers showed decreased attention and execution functions compared with noncarriers (GG/GT). Regarding the topological alterations of the brain connectome, the risk allele group exhibited reduced global and local efficiency of white matter structural networks, mainly in the left anterior and posterior cingulate cortices (PCC). Importantly, the efficiency of the left PCC is correlated with the impaired attention function and mediates the impacts of the rs405509 genotype on attention. These results demonstrated that the rs405509 polymorphism affects attention function in nondemented elderly people, possibly by modulating brain structural connectivity of the PCC. This polymorphism may help us to understand the neural mechanisms of cognitive aging and to serve as a potential marker assessing the risk of AD. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (APOE) promoter polymorphisms have long been linked to Alzheimer disease (AD) susceptibility, although the established data remains controversial. Using meta-analysis, our study aimed to clarify the nature of the genetic risks contributed by the three polymorphisms for developing AD. Medline, Embase, and Alzgene search identified 40 studies with 9,662 cases and 9.696 controls. Both -491A/T polymorphism (AA vs AT + TT: OR = 1.49, 95% CI=1.29–1.72) and -219T/G polymorphism (TT vs TG + GG: OR=1.30, 95% CI=1.10–1.55) showed a significant association with AD susceptibility; however, significant association was not identified in the analysis for -427T/C polymorphism (TT vs TC + CC: OR =1.03, 95% CI= 0.82–1.30). Among the APOE ℇ 4} carriers, the -491A homozygotes were at higher risk to develop AD compared with the -491T carriers (OR=1.42, 95% CI =1.15–1.76). For subjects carrying the -491AA genotype, the presence of the APOE ℇ4 allele increased the risk of AD 4.37-fold (95% CI=3.43–5.56). Subgroup analysis restricted to the late-onset or the Caucasian individuals revealed a similar association as that identified without restriction regarding -491A/T polymorphism. Our results confirm a significant but modest association between APOE promoter -491A/T and -219T/G polymorphisms and AD susceptibility. [ABSTRACT FROM AUTHOR]

The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be ɛ4-independent risk factors for Alzheimer's disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/ɛ4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.European Journal of Human Genetics (2009) 17, 938–945; doi:10.1038/ejhg.2008.263; published online 28 January 2009 [ABSTRACT FROM AUTHOR]

Hepatocyte-directed delivery of therapeutic genes is a major field of gene therapy. An important issue in this context is the availability of promoters units providing for maximum transcriptional activity and specificity. Although a number of liver-specific promoters and transcriptional control elements have been identified and used for gene delivery, no systematic study has been performed to identify the best suitable combination of known liver-specific promoter and enhancer elements. We now report the results of a comparative investigation addressing this issue. We tested a total of 25 synthetic transcriptional control units consisting of either of the four core promoters from liver-specific genes linked in various combinations and configurations to hepatocyte-specific enhancer elements. These constructs were analyzed for transcriptional activity in different cell types in cell culture and in mouse liver in vivo. The data lead to the clear conclusion that a combination of the alcohol dehydrogenase 6 (ADH6) basal promoter linked to two tandem copies of an apoplipoprotein E enhancer element is the transcriptional control unit of choice for the liver-specific expression of transgenes. [Copyright &y& Elsevier]

Objective:. To investigate the association between apolipoprotein E (APOE) polymorphisms and the progression of MS. Methods:. We investigated 428 subjects affected by clinically defined MS, with a disease duration of at least three years. We collected data concerning the age at onset of MS, clinical type, disease duration and disability according to the expanded disability status scale (EDSS). We also calculated the progression index (PI) to evaluate disease progression. APOE genotyping and the –491 A/T polymorphism of the APOE promoter were determined. Results:. No association was observed between the APOE ε4 allele and clinical characteristics of our study population. We also investigated the –491 A/T APOE promoter polymorphism in 236 MS subjects and did not find any association between the –491 A/T polymorphism and the selected clinical variables. Conclusions:. In our population the APOE ε4 allele and the –491 A/T APOE promoter polymorphism are not associated with a more rapid course of MS. [ABSTRACT FROM AUTHOR]

Abstract Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly. Predominantly this disease is sporadic in nature with only a small percentage of patients exhibiting a familial trait. Early-onset AD may be explained by single gene defects; however, most AD cases are late onset (> 65 years) and, although there is no known definite cause for this form of the disease, there are several known risk factors. Of these, the ε4 allele of the apolipoprotein E (apoE) gene (APOE ) is a major risk factor. The ε4 allele of APOE is one of three (ℇ2 ℇ3 and ℇ4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites. The possession of the ℇ4 allele is recognized as the most common identifiable genetic risk factor for late-onset AD across most populations. Unlike the pathogenic mutations in the amyloid precursor or those in the presenilins, APOE ℇ4 alleles increase the risk for AD but do not guarantee disease, even when present in homozygosity. In addition to the cysteine/arginine polymorphisms at the ℇ2/ℇ3/ℇ4 locus, polymorphisms within the proximal promoter of the APOE gene may lead to increased apoE levels by altering transcription of the APOE gene. Here we review the genetic and biochemical evidence supporting the hypothesis that regulation of apoE protein levels may contribute to the risk of AD, distinct from the well known polymorphisms at the ℇ2/ℇ3/ℇ4 locus. [ABSTRACT FROM AUTHOR]

Polymorphisms of the apolipoprotein E (APOE) promoter rs405509 are related to Alzheimer's disease (AD). The T/T allele of rs405509 decreases the transcription of the APOE gene and leads to impairments in a specific brain structural network in aged individuals; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects white matter networks during aging. Here, we investigated the effect of the rs405509 genotype (T/T versus G-allele) on age-related brain white matter structural networks via construction of the graph theory-based structural connectome using diffusion MRI data in a large cohort. Network communication efficiency was quantified, along with the network's betweenness centrality (Bc), global efficiency, local efficiency, and shortest path length. Regarding cognition, TT carriers had significant negative correlations between age and memory performance and between age and executive functions. A network analysis showed that TT carriers had an accelerated age-related loss of Bc and that regional Bc decreased in the left inferior frontal gyrus pars opercularis, the left posterior cingulate cortex, the right inferior occipital gyrus (IOG.R), and the left angular gyrus (ANG.L). Additional brain-behavior relationship analyses showed that polymorphism of rs405509 and age have strong interaction effects on the association of nodal Bc and cognition, mainly in the IOG.R and ANG.L. These results demonstrate that the rs405509 T/T allele of APOE causes an age-related cognitive decline in non-demented elderly people, possibly by modulating brain network communication efficiency, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis.