Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down Syndrome

Prasher, V. P.; Sajith, Sreedharan Geetha; Rees, Simon D.; Patel, Ashok Kumar; Tewari, Satyendra; Schupf, Nicole; Zigman, Warren B.

doi:10.1002/gps.2039

Cited by 72 publications

(74 citation statements)

References 38 publications

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“…The APOE e4 allele has been shown to increase risk for developing AD in both the DS (Coppus et al, 2008;Prasher et al, 2008;Rohn et al, 2014) and TD populations (Bertram and Tanzi, 2008;Corder et al, 1993;Liu et al, 2015). The observed e4 carrier frequency was 5 out of 54 alleles, or 9%, which is similar to the frequency observed in the general population (13%) (Bertram and Tanzi, 2008;Corder et al, 1993;Liu et al, 2015).…”

Section: Exploratory Analyses In Dsmentioning

confidence: 55%

Resting-State Functional Connectivity in Individuals with Down Syndrome and Williams Syndrome Compared with Typically Developing Controls

et al. 2015

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The emergence of resting-state functional connectivity (rsFC) analysis, which examines temporal correlations of low-frequency ( < 0.1 Hz) blood oxygen level-dependent signal fluctuations between brain regions, has dramatically improved our understanding of the functional architecture of the typically developing (TD) human brain. This study examined rsFC in Down syndrome (DS) compared with another neurodevelopmental disorder, Williams syndrome (WS), and TD. Ten subjects with DS, 18 subjects with WS, and 40 subjects with TD each participated in a 3-Tesla MRI scan. We tested for group differences (DS vs. TD, DS vs. WS, and WS vs. TD) in between-and within-network rsFC connectivity for seven functional networks. For the DS group, we also examined associations between rsFC and other cognitive and genetic risk factors. In DS compared with TD, we observed higher levels of between-network connectivity in 6 out 21 network pairs but no differences in within-network connectivity. Participants with WS showed lower levels of within-network connectivity and no significant differences in between-network connectivity relative to DS. Finally, our comparison between WS and TD controls revealed lower within-network connectivity in multiple networks and higher betweennetwork connectivity in one network pair relative to TD controls. While preliminary due to modest sample sizes, our findings suggest a global difference in between-network connectivity in individuals with neurodevelopmental disorders compared with controls and that such a difference is exacerbated across many brain regions in DS. However, this alteration in DS does not appear to extend to within-network connections, and therefore, the altered between-network connectivity must be interpreted within the framework of an intact intra-network pattern of activity. In contrast, WS shows markedly lower levels of within-network connectivity in the default mode network and somatomotor network relative to controls. These findings warrant further investigation using a taskbased procedure that may help disentangle the relationship between brain function and cognitive performance across the spectrum of neurodevelopmental disorders.

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Section: Exploratory Analyses In Dsmentioning

confidence: 55%

Resting-State Functional Connectivity in Individuals with Down Syndrome and Williams Syndrome Compared with Typically Developing Controls

et al. 2015

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“…Polymorphisms in genes with important functions in LOAD have similar roles in the development of AD-DS; for example, the apolipoprotein E (APOE) ε4 allele is associated with greater Aβ deposition, as well as with earlier onset and increased risk of AD-DS, whereas the APOE ε2 allele leads to reduced Aβ deposition and a lower risk of disease [132][133][134][135][136][137][138] . Similarly, variants of phosphatidylinositol-binding clathrin assembly protein (PICALM) and sortilin-related receptor 1 (SORL1) influence age of onset in AD-DS, as they do in LOAD 132,139,140 , further supporting the theory that common mechanisms underlie both diseases.…”

Section: Genes Involved In Loadmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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“…Se han encontrado frecuencias significativamente elevadas del alelo APOEε4 y significativamente bajas del alelo APOEε2 en individuos con síndrome de Down que desarrollan enfermedad de Alzheimer antes de los 50 años de edad, comparados con individuos con síndrome que permanecen cognitivamente no afectados y con la población normal (22)(23)(24). En pruebas neuropsicológicas aplicadas a individuos adultos no dementes con síndrome de Down, se observó que la habilidad verbal estaba inversamente relacionada con la presencia de, al menos, un alelo APOEε4.…”

Section: Polimorfismos De Apoe En El Síndrome De Downunclassified

“…Los cambios cognitivos relacionados con la edad en individuos con el síndrome no dementes, correspondieron con los cambios cognitivos tempranos de los individuos normales con enfermedad de Alzheimer (25). Además, el alelo APOEε4 se ha asociado con mortalidad temprana y el alelo APOEε2 con longevidad, tanto en la población general como en individuos con síndrome de Down (24,26,27). Sin embargo, estudios similares de casos y controles, grupos familiares y por reportes de metaanálisis, no se ha encontrado asociación de los polimorfismos del gen ApoE en individuos con síndrome de Down (28)(29)(30)(31).…”

Section: Polimorfismos De Apoe En El Síndrome De Downunclassified

Polimorfismos del gen ApoE en individuos con síndrome de Down y sus progenitores en una población colombiana

2012

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Introducción. Los polimorfismos en el gen ApoE se han examinado en el síndrome de Down debido a la relación existente de la isoforma E4 con la demencia de tipo Alzheimer que aparece en los individuos con síndrome de Down. Objetivos. Determinar los polimorfismos en el gen ApoE en individuos con síndrome de Down y sus progenitores, y buscar su asociación. Materiales y métodos. Mediante PCR-RFLP, se analizaron los polimorfismos del gen ApoE en 134 individuos jóvenes con síndrome de Down, 87 madres y 54 padres del eje cafetero, y se compararon con una población control de 525 individuos sanos. Resultados. El alelo APOEε3 y el genotipo ε3/ε3 fueron los más frecuentes en todas las poblaciones. La frecuencia alélica de APOEε2 es muy baja y ε2/ε2 está ausente en las poblaciones con síndrome de Down y sus progenitores. El alelo APOEε4 fue más frecuente en individuos con síndrome de Down que en el resto de poblaciones analizadas. Al comparar las frecuencias alélicas y genotípicas entre las poblaciones con síndrome de Down y los progenitores con la población control, mediante la χ 2 de Pearson y los odds ratios por la prueba exacta de Fisher, no se encontraron diferencias estadísticamente significativas. Conclusiones. No se encontró asociación entre los polimorfismos del gen ApoE y el síndrome de Down. Es posible que el tamaño de la muestra o las influencias étnicas hubieran afectado estos resultados. Es necesario hacer otros estudios en poblaciones colombianas y evaluar la asociación con otros genes que se encuentran relacionados con la enfermedad de Alzheimer.Palabras clave: apolipoproteínas E, síndrome de Down, enfermedad de Alzheimer, alelos, genotipo, Colombia. APOE gene polymorphisms associated with Down syndrome in Colombian populationsIntroduction. Gene APOEε4 allele polymorphisms have been examined in Down syndrome because of the relationship between (a) the E4 isoform and (b) the type of Alzheimer's dementia that appears in individuals with Down syndrome. This isoform is considered a risk factor for Alzheimer´s disease development and has been associated with early death in Down syndrome. Objectives. The polymorphisms in the APOE gene were characterized for Down syndrome individuals and their parents, in order to detect associations between the APOE polymorphisms and Down syndrome. Materials and methods. APOE gene polymorphisms were detected by RFLP-PCR and analyzed in 134 young individuals with Down syndrome, 87 mothers and 54 fathers, residents of the departments of Quindío and Risaralda, Colombia. The controls were 525 healthy individuals. Results. The APOEε3 allele and ε3/ε3 genotype were most frequent in all the populations (83-90% and 70-78%). The allelic frequency of APOEε2 was very low and ε2/ε2 (3-7%) was absent in Down syndrome and their parents. The allele APOEε4 was more frequent (11% vs. 9%) in Down syndrome individuals than in the controls. Comparing the allelic and genotypic frequencies between the populations with Down syndrome and their parents with the controls using Pearson χ 2 test and Fisher'...

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Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down Syndrome

Cited by 72 publications

References 38 publications

Resting-State Functional Connectivity in Individuals with Down Syndrome and Williams Syndrome Compared with Typically Developing Controls

Resting-State Functional Connectivity in Individuals with Down Syndrome and Williams Syndrome Compared with Typically Developing Controls

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Polimorfismos del gen ApoE en individuos con síndrome de Down y sus progenitores en una población colombiana

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