APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy

Sleegers, Kristel; Brouwers, Nathalie; Gijselinck, Ilse; Theuns, Jessie; Goossens, Dirk; Wauters, J.; Del-Favero, Jurgen; Cruts, Marc; Duijn, Cornelia M. van; Broeckhoven, Christine Van

doi:10.1093/brain/awl203

Cited by 339 publications

(275 citation statements)

References 25 publications

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“…[12][13][14] The association between SMN1 gene copy number and ALS previously found in French and Dutch population corroborated this hypothesis in MND. [2][3][4] As almost all genetic association studies led to controversial results, we aimed to strengthen the findings of an association between SMN1 copy number and SALS in a third unrelated population.…”

Section: Discussionsupporting

confidence: 58%

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

et al. 2012

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Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semiquantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations.

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Section: Discussionsupporting

confidence: 58%

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

et al. 2012

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“…Primers from within the APP promoter, APP5e (exon 5) and APP18i (the intron after exon 18) were used in Sleegers et al 9 Primers for the control genes hemoglobin beta (HBB) on chromosome 11, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on chromosome 12 and ubiquitin C (UBC) on chromosome 12, have previously been used in Johnson et al, 14 West et al 15 and in Sleegers et al, 9 respectively.…”

Section: Allele Quantificationmentioning

confidence: 99%

“…7 Also, two research groups have recently reported that duplications of APP, in the absence of trisomy 21, can cause familial EOAD with cerebral amyloid angiopathy (EOAD/CAA). 8,9 In this study, we screened for APP duplications in affected subjects from Swedish and Finnish families and cases with EOAD in an effort to estimate the frequency of APP duplications in EOAD patients in these populations.…”

Section: Introductionmentioning

confidence: 99%

Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease

et al. 2007

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Familial early-onset Alzheimer's disease with cerebral amyloid angiopathy (EOAD/CAA) was recently associated with duplications of the gene for the amyloid-b precursor protein (APP). In this study, we have screened for duplications of APP in patients with EOAD from Sweden and Finland. Seventy-five individuals from families with EOAD and 66 individuals with EOAD without known familial inheritance were screened by quantitative PCR. On the basis of the initial results, a portion of the samples was also investigated with quantitative multiplex PCR. No duplications of APP were identified, whereby we conclude that this is not a common cause of EOAD in the Swedish and Finnish populations, at least not in our collection of families and cases.

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“…11,13,109 , but currently there are insufficient data on these phenotypes to compare Dup-APP with AD-DS or LOAD. As in AD-DS, there is a greatly increased risk of dementiaassociated seizures in Dup-APP [10][11][12][13]47 , in contrast to LOAD, in which seizures are relatively rare. This suggests that duplication of APP, and possibly of other genes located nearby, could be epileptogenic; however, as late-onset seizures often follow onset of dementia, they may also be related to synaptic deterioration that results in abnormal synchronization of neuronal networks and hyperexcitability 110 .…”

mentioning

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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APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy

Cited by 339 publications

References 25 publications

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

Homozygous SMN2 deletion is a protective factor in the Swedish ALS population

Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease

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

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