Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PP1
Clinical Phenotype: Alzheimer's Disease
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 large Israeli family with 10 members suffering from early onset Alzheimer’s disease and/or intracerebral hemorrhage (Kalfon et al., 2022). The pedigree included 68 individuals spanning seven generations. All of the six demented women who were genotyped and three of four men with intracerebral hemorrhage (ICH) carried the APP duplication. Ages at onset for dementia ranged from 42 to 55 years and for ICH from 43 to 48 years. Initial signs of dementia were anxiety, depression, or psychosis with memory loss. Other cognitive abilities deteriorated shortly afterwards. Six carriers with advanced dementia experienced seizures.

Genetic analyses, including, chromosomal microarray, karyotypying, fluorescence in situ hybridization, and whole genome sequencing, revealed a complex mutation: a 0.71 Mb duplication of chromosome 21, including APP and cysteine/tyrosine-rich protein 1 (CYYR1), together with a 4.6 Mb duplication of chromosome 5. Only one individual with ICH and one with dementia carried the chromosome 21, but not the chromosome 5, duplication. Adding further to the complexity, in most carriers (29 of 32), the duplications appeared to be translocated onto chromosome 18 at the site of MAPK4, a gene encoding a kinase highly expressed in brain and heart. The authors speculated that transposable elements may underlie the origin of the unusual rearrangement. 

The APP duplication segregated with disease as confirmed by five non-carriers who remained asymptomatic past the age of 55, including two over 65. Twenty-two of 23 asymptomatic carriers had not yet reached age of onset, and the one carrier who had reached it, but was not past it, at age 44, had brain microbleeds as assessed by MRI. Also, several asymptomatic carriers showed signs of cognitive decline in their mid-thirties. Seven had neuro-behavioral alterations, with four reporting a life-long history of behavioral and/or emotional disturbances. This contrasts with only one of 25 asymptomatic non-carriers who had intellectual disability. The authors also noted that 36 percent of demented carriers and 13 percent of asymptomatic carriers were diagnosed with potential autoimmune syndromes.

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 data are unavailable, but data from CT and/or MRI scans were reported for five affected and 21 asymptomatic carriers (Kalfon et al., 2022). Four of the five affected carriers had white matter lesions or some form of vascular alteration, as did six of the asymptomatic carriers. The average age of the asymptomatic carriers with apparent pathology was 36, while that of asymptomatic carriers with normal MRI scans was 29. Of note, four of 27 non-carriers also had white matter lesions or bleeding, but they were older: three were in their mid- to late-forties and one was 72. 

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.

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References

News Citations

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

Paper Citations

1. Kalfon L, Paz R, Raveh-Barak H, Salama A, Samra N, Kaplun A, Chasnyk N, Kfir NC, Mousa NK, Biton ES, Tanus M, Aharon-Peretz J, Falik Zaccai TC. Familial Early-Onset Alzheimer's Caused by Novel Genetic Variant and APP Duplication: A Cross-Sectional Study. Curr Alzheimer Res. 2022;19(10):694-707. 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. 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.
6. Lott IT, Head E. Dementia in Down syndrome: unique insights for Alzheimer disease research. Nat Rev Neurol. 2019 Mar;15(3):135-147. PubMed.
7. 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.
8. 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