Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PP1
Clinical Phenotype: Alzheimer's Disease
Coding/Non-Coding: Both
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Genomic Region: Chromosome 21

Findings

This variant, a ~2 Mb duplication of at least 10 genes on chromosome 21 including APP, belongs to the original set of APP duplications first tied to autosomal dominant Alzheimer’s disease (AD) (Rovelet-Lecrux et al., 2006). It was identified in a French family (F009) with early onset AD. Duplications were detected by analyzing the APP locus on chromosome 21 using quantitative multiplex PCR of short fluorescent fragments (QMPSF)—a method that simultaneously amplifies multiple short genomic sequences. The authors suspected an alteration in this region because AD with cerebral amyloid angiopathy (CAA) is often observed in Down syndrome patients who carry an additional chromosome 21 (although neuropathological data for this family were not reported) (see Trisomy 21).

The proband was a man who experienced onset of dementia at age 57 and who died at age 61. His brother, who also carried the duplication, had dementia symptoms starting at age 53 and died at age 67. Both suffered from seizures, three and seven years after dementia onset, and both were APOE3/E4 heterozygotes. The brother also had dyslipidemia and intracerebral hemorrhage.

The mother of the two carriers and other siblings were also affected by dementia and, in one case, by intracerebral hemorrhage too, but their carrier status was unknown. None of the affected individuals had intellectual disability pre-dementia, nor other features of Down syndrome. Of note, two living brothers were non-carriers and remained healthy at ages 60 and 65, confirming the duplication segregated with disease.

APP duplications are rare or absent from the general population (Sharp et al., 2005) and appear to be a rare cause of early onset AD (e.g., Hooli et al., 2012; June 2013 news; Wang et al., 2023).

Neuropathology
Neuropathological data are unavailable.

Biological Effect
The biological effect of this specific APP duplication is unknown, but a study of multiple carriers of APP duplications showed that, as expected, the median levels of APP mRNA in blood were approximately 1.4-fold higher in carriers compared with non-carriers (Pottier et al., 2012). However, variability between duplications and individual carriers suggests other factors, such as the specific genes included in the duplication, may modulate expression (e.g., Lott and Head, 2019).

Of note, APP is in a recombination hotspot harboring multiple low copy repeats that may facilitate APP duplication (Sleegers et al., 2006; Rovelet-Lecrux et al., 2006).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Comments

1. • Andre Delacourte
     Inserm
   • Posted: 02 Jan 2006
   • Paper: APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.

   A great discovery. I agree with John Hardy that this discovery shows, once and for all, the major role of APP dysfunction n Alzheimer disease.

   At first sight, the paper strongly reinforces the amyloid cascade hypothesis. However, in these familial cases, like in all other familial and sporadic AD cases, dementia occurs with a neocortical tauopathy, showing also that AD explanation is more likely an APP-tau deleterious interaction.

   View all comments by Andre Delacourte
2. • Daniel Geschwind
     
   • Posted: 02 Jan 2006
   • Paper: APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.

   The role of copy number polymorphisms in human genetic variation has only recently been appreciated and only investigated in a few diseases. This provides the first evidence that gene copy number abberations, in addition to being a mechanism of Parkinson disease, can be a cause of AD. So, the discovery about a decade ago of the CMT duplication may have been just the tip of the iceberg.

   View all comments by Daniel Geschwind

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References

Mutations Citations

1. Trisomy 21

News Citations

1. Do Copy Number Variations Point to Potential AD Genes? 27 Jun 2013

Paper Citations

1. Sharp AJ, Locke DP, McGrath SD, Cheng Z, Bailey JA, Vallente RU, Pertz LM, Clark RA, Schwartz S, Segraves R, Oseroff VV, Albertson DG, Pinkel D, Eichler EE. Segmental duplications and copy-number variation in the human genome. Am J Hum Genet. 2005 Jul;77(1):78-88. Epub 2005 May 25 PubMed.
2. Hooli BV, Mohapatra G, Mattheisen M, Parrado AR, Roehr JT, Shen Y, Gusella JF, Moir R, Saunders AJ, Lange C, Tanzi RE, Bertram L. Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology. 2012 Apr 17;78(16):1250-7. Epub 2012 Apr 4 PubMed.
3. Wang H, Dombroski BA, Cheng P-L, Tucci A, Si Y-q, Farrell JJ, Tzeng J-Y, Leung YY, Malamon JS, Wang L-S, Vardarajan BN, Farrer LA, Schellenberg GD, Lee W-P. Structural Variation Detection and Association Analysis of Whole-Genome-Sequence Data from 16,905 Alzheimer's Diseases Sequencing Project Subjects. 2023 Sep 13 10.1101/2023.09.13.23295505 (version 1) medRxiv.
4. Pottier C, Wallon D, Lecrux AR, Maltete D, Bombois S, Jurici S, Frebourg T, Hannequin D, Campion D. Amyloid-β protein precursor gene expression in alzheimer's disease and other conditions. J Alzheimers Dis. 2012;28(3):561-6. PubMed.
5. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
6. Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C. APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain. 2006 Nov;129(Pt 11):2977-83. Epub 2006 Aug 18 PubMed.
7. Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006 Jan;38(1):24-6. Epub 2005 Dec 20 PubMed.

Other Citations

1. Rovelet-Lecrux et al., 2006

Further Reading

No Available Further Reading