Overview

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

Findings

This APP duplication was identified in a Finnish family spanning four generations with AD and intracerebral hemorrhage (Rovelet-Lecrux et al., 2007; Remes et al., 2004). Fourteen affected members had cognitive decline starting between ages 40 and 54, and five members had suffered from lobar intracerebral hemorrhage (ICH). Two of the hemorrhagic patients developed seizures. As in other APP duplication families, none of the carriers had clinical features of Down syndrome.

Initial genetic analysis failed to reveal any mutation in the APP gene, although four single nucleotide polymorphisms in the APP locus indicated that affected family members shared a common haplotype (Remes et al., 2004). A subsequent study using quantitative multiplex PCR of short fluorescent fragments (QMPSF), identified a duplication, including the APP and GABPA genes (Rovelet-Lecrux et al., 2007). A total of nine affected subjects and nine healthy spouses were genotyped. The duplication was present in all the affected individuals and none of the controls. Further analysis of the mutation indicated the duplicated region included the genes JAM2, ATP5J, GABPA, and APP, and its minimum size was 0.55Mb. All carriers had an APOE3/E3 genotype.

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
Post-mortem examination of three members of the Finnish family revealed neuropathology consistent with AD and prominent cerebral amyloid angiopathy (Remes et al., 2004).

In addition, five patients had suffered one or more episodes of ICH and, in one 48-year-old man, MRI revealed hemosiderin deposits suggesting previous microbleeds. Interestingly, all the patients with hemorrhagic events were men and the events occurred in the early stages of disease, except for one case: a woman who had ICH 18 years after the onset of cognitive decline.

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, can 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

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

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

Paper Citations

1. Rovelet-Lecrux A, Frebourg T, Tuominen H, Majamaa K, Campion D, Remes AM. APP locus duplication in a Finnish family with dementia and intracerebral haemorrhage. J Neurol Neurosurg Psychiatry. 2007 Oct;78(10):1158-9. Epub 2007 Apr 18 PubMed.
2. Remes AM, Finnilä S, Mononen H, Tuominen H, Takalo R, Herva R, Majamaa K. Hereditary dementia with intracerebral hemorrhages and cerebral amyloid angiopathy. Neurology. 2004 Jul 27;63(2):234-40. PubMed.
3. 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.
4. 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.
5. 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.
6. 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.
7. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
8. 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.
9. 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.

Further Reading

No Available Further Reading