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, a ~4 Mb duplication of at least 12 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; Cabrejo et al., 2006). It was identified in a French family (F019) with early onset AD and cerebral amyloid angiopathy (CAA). 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 CAA is often observed in Down syndrome patients who carry an additional chromosome 21(see Trisomy 21).

The proband was a man with dementia starting at age 42 who died at 46. Three years before dementia onset he had surgery to remove a cervical cluster of blood vessels known as a cavernoma. His mother, who also carried the duplication, had dementia symptoms starting at age 48, suffered from apparent intracerebral hemorrhage, and died at 60. Two of her sisters who were not genotyped also developed dementia, at ages 53 and 59, with the former possibly experiencing cerebral hemorrhage as well. Both the proband and his mother developed seizures—the proband one year after onset of dementia and the mother six years after. The APOE genotype of both was APOE3/E3. None of the affected members had intellectual disability or other features of Down syndrome before dementia onset.

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
Neuropathology in the two carriers was consistent with AD, with abundant amyloid deposits, including dense-core plaque and diffuse deposits, and neurofibrillary tangles in the hippocampal cortex, the limbic system, and the isocortex (Rovelet-Lecrux et al., 2006; Cabrejo et al., 2006). In addition, severe CAA was extensive. Focal areas of demyelination were seen around most blood vessels. Vascular amyloid was predominantly composed of Aβ40. In the mother, ventricular dilation was severe and lacunae and hemorrhages in the temporal and hippocampal gyri were observed, as well as microaneurysms and hemosiderin, particles composed of partially degraded hemoglobin or ferritin.

In addition, brain imaging revealed moderate white matter changes in the parieto-occipital cortex and infra-tentorial region of the proband. SPECT hypoperfusion was diffuse. Atrophy was reported in the parieto-occipital cortex, as well as in the frontal and temporal cortices, although it was more mild in the latter two. The mother had mild atrophy only in the parieto-occipital cortex.

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. 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.

Further Reading

No Available Further Reading