Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
DIAN-TU Eligibility: Yes
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891761 G>C
Position: (GRCh37/hg19):Chr21:27264073 G>C
dbSNP ID: rs63750151
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAG to AAC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17

Findings

This mutation, which is just outside the transmembrane domain of APP, was first described in a Belgian patient who began having memory problems at the age of 55 and fulfilled the criteria of probable AD. She had a family history of dementia. Her father was diagnosed with Pick's disease at the age of 52 and died without autopsy at the age of 56. The proband's symptoms included progressive impairment of episodic memory and executive functioning. Other symptoms included anxiety, depression, and apathy (Theuns et al., 2006).

Although detailed information for the carriers is unavailable, this variant was also identified in individuals in the U.S. and Germany who developed AD with an average age at onset of 46.5 (1.0 std error; Liu et al., 2025). 

This mutation was absent from the gnomAD variant database (v2.1.1, Oct 2021).

Neuropathology

At 56 years of age, the Belgian proband had significantly more amyloid across the cerebral cortex than control subjects as measured by PiB-PET (Theuns et al., 2006). Upon autopsy, at age 66, the diagnosis of AD was confirmed with amyloid and tau pathology, Braak stadium V-VI (Mertens et al., 2013, suppl Table 1).

Biological Effect

A significantly increased Aβ42/Aβ40 ratio was measured in the conditioned media of K724N-transfected HEK293T cells. A similar increase was measured in primary mouse neurons due to an increase in Aβ42 and a decrease in Aβ40 (Theuns et al., 2006). Subsequent studies using transfected neuroblastoma cells (Hsu et al., 2020) and carrier-derived induced pluripotent stem cells (Portelius et al., 2016) yielded similar results.

Also of note, this variant may change the acetylation state of APP which could have implications for AD pathogenesis. Sirtuin 6 (SIRT6) deacetylates APP at three consecutive amino acids, the first being K724 (Dec 2024 news; Cheng et al., 2024). Deacetylation of APP was tied to APP ubiquitination and degradation, and treatment of APP/PS1 mice with a SIRT6 activator reduced both amyloid pathology and memory deficits.

Moreover, the variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021).

The variant has been classified as “pathogenic” by the Dominantly Inherited Alzheimer Network Trials Unit (Liu et al., 2025).

Research Models
Induced pluripotent stem cells were derived from a skin biopsy taken from the carrier described above at age 64 (Mertens et al., 2013).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic*

*Carriers of this variant are eligible for inclusion in clinical trials organized by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) to test disease-modifying treatments for Alzheimer’s disease (Liu et al., 2025).

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. SIRT6 Reported to Destabilize APP 19 Dec 2024

Paper Citations

1. Theuns J, Marjaux E, Vandenbulcke M, Van Laere K, Kumar-Singh S, Bormans G, Brouwers N, Van den Broeck M, Vennekens K, Corsmit E, Cruts M, De Strooper B, Van Broeckhoven C, Vandenberghe R. Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat. 2006 Sep;27(9):888-96. PubMed.
2. Liu H, Marsh TW, Shi X, Renton AE, Bowling KM, Ziegemeier E, Wang G, Cao Y, Aristel A, Li J, Dickson A, Perrin RJ, Goate AM, Fernández V, Day GS, Doering M, Daniels A, Gordon BA, Benzinger TL, Hassenstab J, Ibanez L, Supnet-Bell C, Xiong C, Allegri R, Berman SB, Fox NC, Ryan N, Huey ED, Vöglein J, Noble JM, Roh JH, Jucker M, Laske C, Ikeuchi T, Sanchez-Valle R, Schofield PR, Chrem Mendez P, Chhatwal JP, Farlow M, Lee JH, Levey AI, Levin J, Lopera F, Martins R, Niimi Y, Rosa-Neto P, Morris JC, Bateman RJ, Karch CM, Cruchaga C, McDade E, Llibre-Guerra JJ. The landscape of autosomal-dominant Alzheimer's disease: global distribution and age of onset. Brain. 2025 Feb 4; Epub 2025 Feb 4 PubMed.
3. Mertens J, Stüber K, Wunderlich P, Ladewig J, Kesavan JC, Vandenberghe R, Vandenbulcke M, van Damme P, Walter J, Brüstle O, Koch P. APP processing in human pluripotent stem cell-derived neurons is resistant to NSAID-based γ-secretase modulation. Stem Cell Reports. 2013;1(6):491-8. Epub 2013 Dec 5 PubMed.
4. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
5. Portelius E, Durieu E, Bodin M, Cam M, Pannee J, Leuxe C, Mabondzo A, Oumata N, Galons H, Lee JY, Chang YT, Stϋber K, Koch P, Fontaine G, Potier MC, Manousopoulou A, Garbis SD, Covaci A, Van Dam D, De Deyn P, Karg F, Flajolet M, Omori C, Hata S, Suzuki T, Blennow K, Zetterberg H, Meijer L. Specific Triazine Herbicides Induce Amyloid-β42 Production. J Alzheimers Dis. 2016 Oct 18;54(4):1593-1605. PubMed.
6. Cheng R, Bai N, Liu S, Zhao X, Jiang B, Guo W, Cao S, Liu J, Li N, Li X, Wu X, Yi F, Wang Z, Guo Q, Wei J, Bai M, Jiang X, Song X, Wang Z, Miao Q, Wang D, Di Y, Liu H, Cao L. The deacetylase SIRT6 reduces amyloid pathology and supports cognition in mice by reducing the stability of APP in neurons. Sci Signal. 2024 Dec 10;17(866):eado1035. Epub 2024 Dec 10 PubMed.

Further Reading

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