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 ~0.8 Mb duplication of a stretch of DNA harboring six genes on chromosome 21, from LINC00158 to APP. It belongs to the original set of APP duplications first tied to autosomal dominant Alzheimer’s disease (AD) (Rovelet-Lecrux et al., 2006). The duplication was identified in a French family (F037, a.k.a., ROU-037) 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. 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 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 F037 family had eight affected members with heterogenous clinical phenotypes (Rovelet-Lecrux et al., 2006, Grangeon et al., 2023). Ages at onset ranged from 48 to 59 years, and disease duration from 5 to 12 years. The proband was a woman who experienced onset of dementia at age 53 and who died at age 66. Five of her seven siblings, as well as an affected niece, also carried the duplication and developed dementia. Two of them had lobar hemorrhage, one of whom had cardiovascular disease, and two others had arterial hypertension. The proband, four affected siblings, and the affected niece sufferred from seizures. The father had dementia and the mother had a stroke and died at age 55. Neither of the parents were genotyped. Six family members who were genotyped were APOE3 homozygotes. 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) 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 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).

In addition, severe and extensive CAA was observed. Focal areas of demyelination were seen around most blood vessels. Vascular amyloid was predominantly composed of Aβ40. In a subsequent study that included three carriers of this family, CAA was reported in the temporal, frontal, and occipital cortices involving both leptomeningeal and intraparenchymal arteries (Mann et al., 2018). In two carriers, CAA extended into capillary beds as well, and these individuals had relatively few, mostly cored, amyloid plaques compared with abundant vascular and peri-vascular pathology. They also had severe cerebellar CAA. In contrast, in the third carrier, capillary involvement was very rare and dense perivascular deposits were absent, while Aβ deposits were widespread. The cerebellum of this individual also had CAA, but it was moderate. Of note, a subsequent study reported a carrier with multiple microcalcifications near the amyloid angiopathy within cortical and subcortical occipital regions (Grangeon et al., 2023).

Brain imaging was also used to examine several carriers in this family (Cabrejo et al., 2006). In one individual, SPECT hypoperfusion was diffuse and in another it was localized to the parieto-temporal region. CT scans revealed hemorrhage in two duplication carriers. In one of them, MRI showed severe parieto-occipital white matter changes which were also seen in another carrier with no reported hemorrhage. In the former, post-mortem microscopic analysis revealed microaneurysms. Atrophy in the frontal, parieto-occipital, and temporal areas was reported in several family members. Surprisingly, MRI of one carrier, the proband's niece who had dementia starting at age 48 with seizures, revealed no signs of CAA, with no intracerebral hemorrhages, no cerebral microbleeds, and no 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. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. Mann DM, Davidson YS, Robinson AC, Allen N, Hashimoto T, Richardson A, Jones M, Snowden JS, Pendleton N, Potier MC, Laquerrière A, Prasher V, Iwatsubo T, Strydom A. Patterns and severity of vascular amyloid in Alzheimer's disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer's disease. Acta Neuropathol. 2018 Oct;136(4):569-587. Epub 2018 May 16 PubMed.
7. 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.
8. 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.
9. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
10. 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.

Other Citations

1. Rovelet-Lecrux et al., 2006

Further Reading

No Available Further Reading