Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
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).

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

Neuropathology

At 56 years of age, the 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).

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).

Note on Pathogenicity
Because Alzforum is aware of only one affected carrier of K724N, this variant has not been classified. However, several groups have classified it as pathogenic and, indeed, pathogenicity is supported by several criteria of the ACMG-AMP guidelines (Richards et al., 2015, see below). Moreover, another mutation at the same site, K724M, has been reported in a family with early onset AD (Peng et al., 2014) and was classified as likely pathogenic by Alzforum.

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. K724N: Variant located at edge of mutational hot spot.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 20 Dec 2024

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References

News Citations

Mutations Citations

Paper Citations

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.
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.
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.
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.
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.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.
Peng XL, Hou L, Xu SH, Hua Y, Zhou SJ, Zhang Y, Zheng YP, Fu YH, Xu Q, Zhang LS, Wang J, Guan XT, He JS. Novel APP K724M mutation causes Chinese early-onset familial Alzheimer's disease and increases amyloid-β42 to amyloid-β40 ratio. Neurobiol Aging. 2014 Nov;35(11):2657.e1-2657.e6. Epub 2014 Jun 14 PubMed.

Mutations

APP K724N (Belgian)

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