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 variant is a ~6.4 Mb duplication of a stretch of DNA on chromosome 21 harboring 13 genes, from NCAM2 to EIF4A1P, including APP. It belongs to the original set of APP duplications first tied to autosomal dominant Alzheimer’s disease (AD) (Rovelet-Lecrux et al., 2006; Cabrejo et al., 2006).  The duplication was identified in a French family (F229, a.k.a. ALZ-229) 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 early onset AD is often observed in Down's syndrome patients who carry an additional chromosome 21 (see Trisomy 21). Fluorescence in situ hybridization in lymphocytes confirmed the duplication, revealing three spots in interphase nuclei and, in mitotic cells, an enlarged spot on one chromosome 21 consistent with a segmental duplication.

The proband was a 59-year-old man with dementia that started at age 57. His 62-year-old sister, who also carried the duplication, had dementia symptoms starting at age 52 and also suffered from arterial hypertension. Both were APOE3 homozygotes. Another sister, who was not genotyped, also had arterial hypertension and started with dementia symptoms at age 55, followed by intracerebral hemorrhage and seizures before her death at age 59. An additional, non-genotyped sister died after status epilepticus at age 50 without signs of cognitive decline or behavioral impairment, and a CT scan did not reveal a focal lesion. The mother died of stroke at age 72 and the father died at age 83. Neither were genotyped. Ages at onset for affected members ranged between 52 and 69 years of age (Grangeon et al., 2023).

None of the living affected members had clinical features of Down syndrome, nor did retrospective examination of the medical records reveal signs of the condition in other family members.

APP duplications are rare or absent from the general population (Sharp et al., 2005). Campion and colleagues noted that in their cohort of autosomal dominant early onset AD families, approximately 8 percent (5 of 65) carried an APP duplication (Rovelet-Lecrux et al., 2006). However, overall, APP duplications appear to be a very rare cause of early onset AD (e.g., Hooli et al., 2012; June 2013 news; Wang et al., 2023).

Neuropathology
Neuropathological data are unavailable, but SPECT hypoperfusion was observed in the temporal cortex of the proband and diffuse hypoperfusion was seen in his sister who was also a duplication carrier. In addition, MRI revealed symmetrical parieto-occipital and frontal white matter changes in the proband (Cabrejo et al., 2006). Atrophy was severe in the parieto-temporal cortices of both carriers. In a subsequent study, MRI of the proband was reported as revealing probable cerebral amyloid angiopathy with one intracerebral hemorrhage, 28 cerebral microbleeds, and three instances of cortical superficial siderosis (Grangeon et al., 2023). 

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. 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.
2. Cabrejo L, Guyant-Maréchal L, Laquerrière A, Vercelletto M, De la Fournière F, Thomas-Antérion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D. Phenotype associated with APP duplication in five families. Brain. 2006 Nov;129(Pt 11):2966-76. Epub 2006 Sep 7 PubMed.
3. Grangeon L, Charbonnier C, Zarea A, Rousseau S, Rovelet-Lecrux A, Bendetowicz D, Lemaitre M, Malrain C, Quillard-Muraine M, Cassinari K, Maltete D, Pariente J, Moreaud O, Magnin E, Cretin B, Mackowiak MA, Sillaire AR, Vercelletto M, Dionet E, Felician O, Rod-Olivieri P, Thomas-Antérion C, Godeneche G, Sauvée M, Cartz-Piver L, Le Ber I, Chauvire V, Jonveaux T, Balageas AC, Laquerriere A, Duyckaerts C, Vital A, de Paula AM, Meyronet D, Guyant-Marechal L, Hannequin D, Tournier-Lasserve E, Campion D, CNR-MAJ collaborators, Nicolas G, Wallon D. Phenotype and imaging features associated with APP duplications. Alzheimers Res Ther. 2023 May 11;15(1):93. PubMed.
4. 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.
5. 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.
6. 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.
7. 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.
8. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
9. 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.

Further Reading

No Available Further Reading