Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

Hooli, Basavaraj; Kovács-Vajna, Zsolt Miklós; Mullin, Kristina; Blumenthal, M A; Mattheisen, Manuel; Zhang, C; Lange, Christoph; Mohapatra, Gayatry; Bertram, Lars; Tanzi, Rudolph E.

doi:10.1038/mp.2013.77

Cited by 82 publications

(69 citation statements)

References 74 publications

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Section: Triplication Of Appmentioning

confidence: 99%

“…They therefore differ from other forms of familial AD that are the result of mutations in APP, PSEN1 or PSEN2 that modulate the processing of APP and the generation of Aβ. In Dup-APP, regions of chromosome 21 triplication vary in size [8][9][10][11][12][13][14][15]47,107,108 (FIG. 2); the smallest known duplication contains only an additional copy of APP and no other coding genes 8 .…”

Section: Ad-ds Versus Dup-app-associated Admentioning

confidence: 99%

“…The key dosage-sensitive gene for AD-DS is likely to be APP, as an additional normal copy of this gene is sufficient to cause EOAD in the absence of trisomy of the rest of chromosome 21 (REFS [8][9][10][11][12][13][14][15]47,107). The additional copy of APP in DS does not typically cause substantial Aβ accumulation until the second or third decade of life, although amyloid pathology has been demonstrated in a few childhood post-mortem examinations (BOX 1; FIG.…”

Section: Triplication Of Appmentioning

confidence: 99%

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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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Section: Triplication Of Appmentioning

confidence: 99%

Section: Ad-ds Versus Dup-app-associated Admentioning

confidence: 99%

Section: Triplication Of Appmentioning

confidence: 99%

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

et al. 2015

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“…Among these susceptibility genes, the apolipoprotein E (APOE) gene (19q13.2) (AD2) is the most prevalent as a risk factor for AD, especially in those subjects harboring the APOE-4 allele [12,13], whereas carriers of the APOE-2 allele are prone to longevity [14] and might be protected against dementia [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…The main aims of the study were: (i) structural analysis of the APOE-TOMM40 region (distribution and frequency of major genotypes, with special emphasis on TOMM40 poly T variants) in the Spanish population with dementia; and (ii) APOE-and TOMM40 poly T1/T2-related therapeutic response to a multifactorial therapy in AD. 12 , 10 µg/day; nicotinamide, 50 mg/day), respectively, to maintain stable levels of serum iron (50-150 µg/mL), folic acid (5-20 ng/mL) and vitamin B 12 levels (500-1000 pg/mL) in order to avoid the negative influence of these metabolic time. Blood pressure, psychometric assessment (Mini-Mental State Examination, MMSE; Alzheimer's Disease Assessment Scale, ADAS; Hamilton Rating Scale-Depression, HAM-D; Hamilton Rating ScaleAnxiety, HAM-A), and blood parameters Table 1 were evaluated prior to treatment (baseline) and after 1, 3, 6, 9, and 12 months of treatment.…”

Section: Introductionmentioning

confidence: 99%