APP K670_M671delinsNL (Swedish)

Other Names: Swedish


Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP1, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27269939 G>T, Chr21:27269938 A>C
dbSNP ID: rs63751263, rs63750445
Coding/Non-Coding: Coding
Mutation Type: Point, Double
Codon Change: AAG to AAT, ATG to CTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16
Research Models: 76


The only known mutation immediately adjacent to the β-secretase site in APP, the Swedish mutation is actually a double mutation, resulting in a substitution of two amino acids, lysine (K) and methionine (M) to asparagine (N) and leucine (L). This well-known mutation has been reported in two large Swedish families who were found to be connected genealogically. Affected individuals generally presented first with memory loss and all met diagnostic criteria for Alzheimer's disease (Mullan et al., 1992).

The two substitutions underlying this mutation are absent from the gnomAD variant database (gnomAD v.2.1.1, Oct 2021).


Generalized atrophy with sulcal widening and mild ventricular enlargement was observed in one autopsied case (Mullan et al., 1992).

Biological Effect

In vitro, this mutation repeatedly has been shown to increase total Aβ levels. Specifically, there is increased production and secretion of Aβ40 and Aβ42 (Scheuner et al., 1996; Nilsberth et al., 2001; Ancolio et al., 1999; Johnston et al., 1994; Citron et al., 1994; Citron et al., 1992; Cai et al., 1993). The ratio of Aβ40/Aβ42 is generally not affected.

Interestingly, in human cultured neurons expressing this variant, synapse numbers increased by 20 percent and, correspondingly, synaptic transmission rose (Oct 2022 news; Zhou et al., 2022). The effect appeared to be mediated by Aβ monomer peptides.

The PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 for each of the substitutions, suggesting that, at least individually, they have deleterious effects (CADD v.1.6, Oct 2021).


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.


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


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


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.


Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. K670_M671delinsNL: Cosegregation demonstrated in >1 family.


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. K670_M671delinsNL: Each substitution comprising this variant has a CADD score >20.

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

Research Models

The Swedish mutation is commonly introduced into mouse models of AD because it strongly enhances overall Aβ production. Mice carrying this mutation, such as the Tg2576, J20, and 3xTg models, among many others, tend to accumulate high levels of Aβ and develop amyloid pathology. Of note, the targeting of the Swedish mutation in two mouse models using CRISPR technology resulted in reduced plaques, gliosis, neurite dystrophy, and cognitive decline (Dec 2021 news, Duan et al., 2021). 

Last Updated: 13 Jan 2023


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Research Models Citations

  1. Tg2576
  2. J20 (PDGF-APPSw,Ind)
  3. 3xTg

News Citations

  1. In Mice, Gene Editing Neutralizes Mutant APP, Keeps Plaques Away
  2. In Cultured Human Neurons, Aβ Spurs Synapse Growth

Paper Citations

  1. . Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer's disease alleviates amyloid-related pathologies in mice. Nat Biomed Eng. 2021 Jul 26; PubMed.
  2. . A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992 Aug;1(5):345-7. PubMed.
  3. . Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996 Aug;2(8):864-70. PubMed.
  4. . The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.
  5. . Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24. PubMed.
  6. . Increased beta-amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the Swedish Alzheimer's disease APP670/671 mutation. FEBS Lett. 1994 Nov 14;354(3):274-8. PubMed.
  7. . Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11993-7. PubMed.
  8. . Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992 Dec 17;360(6405):672-4. PubMed.
  9. . Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993 Jan 22;259(5094):514-6. PubMed.
  10. . Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease. Sci Transl Med. 2022 Oct 19;14(667):eabn9380. PubMed.

Further Reading

Protein Diagram

Primary Papers

  1. . A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992 Aug;1(5):345-7. PubMed.


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