Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series

Abstract

Amyloid precursor protein gene (APP) duplications have been identified in screens of selected probands with early onset familial Alzheimer's disease (FAD). A causal role for copy number variation (CNV) in the prion protein gene (PRNP) in prion dementias is not known. We aimed to determine the prevalence of copy number variation in APP and PRNP in a large referral series, test a screening method for detection of the same, and expand knowledge of clinical phenotype. We used a 3-tiered screening assay for APP and PRNP duplication (exonic real-time quantitative polymerase chain reaction [exon-qPCR], fluorescent microsatellite quantitative PCR [fm-q-PCR], and Illumina array [Illumina Inc., San Diego, CA, USA]) for analysis of a heterogeneous referral series comprising 1531 probands. Five of 1531 probands screened showed APP duplication, a similar prevalence to APP missense mutation. Real-time quantitative PCR and fluorescent microsatellite quantitative PCR were similar individually but are theoretically complementary; we used Illumina arrays as our reference assay. Two of 5 probands were from an autosomal dominant early onset Alzheimer's disease (familial Alzheimer's disease) pedigree. One extensive, noncontiguous duplication on chromosome 21 was consistent with an unbalanced translocation not including the Down's syndrome critical region. Seizures were prominent in the other typical APP duplications. A range of imaging, neuropsychological, cerebrospinal fluid, and pathological findings are reported that extend the known phenotype. APP but not PRNP duplication is a significant cause of early onset dementia in the UK. The recognized phenotype may be expanded to include the possibility of early seizures and apparently sporadic disease which, in part, may be due to different mutational mechanisms. The pros and cons of our screening method are discussed.

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

“…Of note, APP duplications were previously identified in patients with familial EOAD and/or cerebral amyloid angiopathy with an AOO before 65 years in our series (61 patients from 12 families), 1 as well as in the UK series with broader inclusion criteria, 21 suggesting that our national guidelines would have allowed identifying all or nearly all APP duplications among the samples referred to our center. APP duplications have sparsely been identified in sporadic cases of early-onset cerebral amyloid angiopathy but were not systematically assessed in EOAD sporadic patients, to our knowledge.…”

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

“…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 duplication of APP (Dup-APP) -also develop EOAD [8][9][10][11][12][13][14][15] . Conversely, partial trisomy of chromosome 21 that does not result in the presence of an extra APP does not lead to AD 16,17 .…”

“…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 .…”

“…Thus, a possible protective mechanism (or mechanisms) from triplication of an unknown gene (or genes) on chromosome 21 may be important for resistance to dementia in people with DS. Moreover, intracerebral haemorrhage (ICH) is common in individuals with Dup-APP (occurring in 20-50% of cases) [9][10][11][12][13][14]47,108 , whereas individuals with DS are generally protected from this pathology, with only occasional reports. Thus, triplication of a chromosome 21 gene (or genes) may protect against some AD co-morbidity, and further comparative study of AD-DS and Dup-APP is required to understand the mechanisms underpinning this observation.…”

“…Clinical DLB and cortical Lewy bodies have been observed in a few cases 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 .…”