Overview

Pathogenicity: Alzheimer's Disease : Pathogenic, Cerebral Amyloid Angiopathy, Dementia with Lewy Bodies : Not Classified
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Dementia with Lewy Bodies
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 French family with Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and dementia with Lewy bodies (DLB) (Guyant-Merchal et al., 2008). The proband was a woman who developed symptoms suggestive of DLB beginning at age 44. She initially had bradykinesia, memory loss, and apraxia, followed by paranoid delusion with visual hallucinations at age 50. She also suffered from bilateral tremor and rigidity, and died at age 55.

Six family members were affected including the proband, her mother, her daughter, a sister, a maternal aunt, and the aunt’s son (Grangeon et al., 2023). All affected individuals developed dementia, with three also having seizures, three having lobar hemorrhages, and one, the proband, experiencing psychosis. Ages at onset ranged from 44 to 58 years and disease duration ranged from five to 32 years.

A ~0.55Mb duplication including four genes—JAM2, ATP5J, GABPA, and APP—was found in the proband and four affected family members. It was also identified in one of the proband’s deceased brothers who remained asymptomatic at 38 years of age.

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 examination of the proband’s brain confirmed the DLB diagnosis and revealed it was associated with AD pathology and severe CAA (Guyant-Merchal et al., 2008). Lewy bodies were found in multiple brain regions including the substantia nigra, locus coeruleus, parahippocampal gyrus, insula, and throughout the cerebral cortex.

In a subsequent study, CAA was reported in temporal, frontal, and occipital cortices involving both leptomeningeal and intraparenchymal arteries (Mann et al., 2018). CAA extended into capillary beds as well, and there were relatively few, mostly cored, amyloid plaques compared with abundant vascular and peri-vascular pathology. CAA was also severe in the cerebellum.

Consistent with the diverse clinical phenotypes observed in patients, MRI scans of three symptomatic carriers revealed substantial heterogeneity. Although all carriers had probable CAA, cerebral microbleeds ranged from 42 to 420 (Grangeon et al., 2023). Also, one carrier had CAA-related inflammation (Chamard et al., 2013). The range of observed intracerebral hemorrhages was one to two (Grangeon et al., 2023). White matter changes were observed in the proband, as well as in an individual with visual seizures (Mann et al., 2018).

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.

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References

News Citations

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

Paper Citations

1. Guyant-Marechal I, Berger E, Laquerrière A, Rovelet-Lecrux A, Viennet G, Frebourg T, Rumbach L, Campion D, Hannequin D. Intrafamilial diversity of phenotype associated with app duplication. Neurology. 2008 Dec 2;71(23):1925-6. PubMed.
2. 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.
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. 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. Chamard L, Wallon D, Pijoff A, Berger E, Viennet G, Hannequin D, Magnin E. Amyloid-related imaging abnormalities in AβPP duplication carriers. J Alzheimers Dis. 2013;37(4):789-93. 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.
11. 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

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