Mutations

APP K670_M671delinsNL (Swedish)

Other Names: Swedish

Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP1, PP3, BS1
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
DNA Change: Deletion-Insertion
Expected RNA Consequence: Deletion-Insertion
Expected Protein Consequence: Deletion-Insertion
Codon Change: AAG to AAT, ATG to CTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16
Research Models: 82

Findings

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).

Interestingly, although the two substitutions underlying this mutation are absent from the gnomAD variant database (gnomAD v.2.1.1, Oct 2021), they were identified in seven individuals of European ancestry, including a homozygous woman from Tuscany (subject NA20259), in the Phase 3 dataset from the 1000 Genome Project Consortium (Abondio et al., 2023). This dataset included sequences of 2,504 ostensibly healthy individuals from 26 worldwide populations. The examination of neighboring sequences revealed a shared haplotype between a carrier of central European ancestry and a British carrier.

Neuropathology

Generalized atrophy with sulcal widening and mild ventricular enlargement was observed in one autopsied case (Mullan et al., 1992). Subsequent studies have revealed AD pathology with cerebral amyloid angiopathy (CAA) in four cases (Welander et al., 2009). Of note, both Aβ42 and Aβ43 have been found in amyloid plaque lesions of at least five cases with the APP Swedish mutation (Welander et al., 2009, Sandebring et al., 2013). In one case, extremely high Aβ40, high Aβ43, and moderate Aβ42 were reported (Sandebring et al., 2013).

Biological Effect

Several mouse models expressing this mutation have impaired memory and learning, increased Aβ production, formation of amyloid plaques, and synaptic loss (e.g., Hsiao et al., 1996, Dong et al., 2007). The synaptic effects of this mutation remain unclear, however. In one study of human cultured neurons, surprisingly, 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 peptides specifically in monomeric form. However, another study failed to detect an effect on synaptogenic activity in a co-culture of HEK cells and mouse primary cortical neurons (Schilling et al., 2023).

The Swedish mutation has been associated with several disruptions of neuronal function at the cellular level. For example, in a preprint, Ma and colleagues reported that wildtype APP, and to a greater extent APP carrying the Swedish mutation, shorten and shift the axon initial segment away from the cell body, likely reducing neuronal excitability (Ma et al., 2023). Moreover, neurons derived from mutant induced pluripotent stem cells were found to be deficient at endocytosing and sorting APP and lipoproteins, with disrupted transport to axons (Woodruff et al., 2016, Oct 2016 news). Also, the Swedish mutation was reported to disrupt both the anterograde and retrograde axonal transport machinery, impairing the movement of multiple vesicles within axons, including APP-loaded vesicles, a subset of early endosomes, and lysosomes (Feole et al., 2024).    

Early studies in transfected human embryonic kidney cells suggested the Swedish mutation also alters the localization of APP processing. Instead of Aβ being generated after secretion and reinternalization of APP, it appeared to be processed in Golgi-derived vesicles resulting in BACE cleavage competing with α-secretase activity in the same compartment (Haass 1995, Thinakaran 1996). However, another study, using the same cell type, did not detect an effect of the mutation on APP localization in the cis-Golgi compartment, early endosomes, or at the cell surface, and found α-secretase cleavage to be similar to that of the wildtype protein (Schilling et al., 2023).

The amino acid substitutions of the Swedish mutation are directly N-terminal to the β-secretase cleavage site and, in vitro, they have been repeatedly shown to increase total Aβ levels by facilitating APP cleavage by BACE1. Showing a much higher affinity for the mutant, compared with wildtype APP (Barman et al., 2011 21500768), BACE1 dominates the processing of Swedish APP (Schilling et al., 2023). It appears to favor cleavage at the M671-D672 bond—which generates amyloidogenic Aβ(1-XX) peptides—rather than the T681-Q682 bond, which generates amyloidolytic Aβ(11-XX) peptides (Kimura et al., 2016). While other familial AD mutations in APP and the presenilins skew Aβ production to larger, more aggregation-prone forms, the Swedish mutation increases overall production of Aβ(1-XX)  with multiple reports showing 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 not affected. 

The Swedish mutation also alters production of other APP-derived peptides. As described above, in one autopsy case, extremely high Aβ40, high Aβ43, and moderate Aβ42 were observed which the authors suggested could indicate an alteration of γ-secretase processing, specifically a preference for the Aβ49→Aβ46→Aβ43→Aβ40 pathway (Sandebring et al., 2013). This is consistent with in vitro studies showing a relative decrease in Aβ38 (Schilling et al., 2023). In rat knockin models, however, the mutation increased the levels of peptides from both major γ-secretase trimming pathways: Aβ43, Aβ40, and Aβ38 (Tambini et al., 2023). Of note, elevated levels of Aβ43 in particular were reported to determine the onset of pathological amyloid deposition in knockin rat models used in this study.

Increased levels of several short N-terminal Aβ peptides, including Aβ1-14, Aβ1-15, Aβ1-16, and Aβ1-19, and particularly Aβ1-17, have also been observed (Schilling et al., 2023). As noted by the authors, BACE1 and consecutive BACE2 cleavage might be responsible for generation of Aβ1-19. Fragments Aβ1-16 and Aβ1-17, on the other hand, may result from cleavages by α-secretase. The increase in Aβ1-17 could result from a secondary cut of the β-CTF by α-secretase. Other proteases, such as cathepsin B and MMP9, could be involved in the production of Aβ16 and other fragments.

Of note, the elevated levels of β-CTF resulting from enhanced BACE activity may be important contributors to pathogenicity. In iPSCs, the Swedish mutation, among other familial AD mutations, was shown to promote the accumulation of APP β-C-terminal fragments which resulted in enlarged endosomes (Kwart et al., 2019, Aug 2019 news).

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).

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.

PS3-S

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

PM1-M

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

PP1-S

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.

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

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  K670_M671delinsNL: Although absent from gnomAD, 7 carriers of European ancestry were identified in the Phase 3 dataset from the 1000 Genome Project Consortium.

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 Mar 2024

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References

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
  3. Cholesterol Trafficking Takes a Hit in Alzheimer’s Neurons
  4. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes

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. . Rare Amyloid Precursor Protein Point Mutations Recapitulate Worldwide Migration and Admixture in Healthy Individuals: Implications for the Study of Neurodegeneration. Int J Mol Sci. 2022 Dec 14;23(24) PubMed.
  4. . Abeta43 is more frequent than Abeta40 in amyloid plaque cores from Alzheimer disease brains. J Neurochem. 2009 Jul;110(2):697-706. Epub 2009 May 15 PubMed.
  5. . The pathogenic aβ43 is enriched in familial and sporadic Alzheimer disease. PLoS One. 2013;8(2):e55847. Epub 2013 Feb 11 PubMed.
  6. . Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996 Oct 4;274(5284):99-102. PubMed.
  7. . Spatial relationship between synapse loss and beta-amyloid deposition in Tg2576 mice. J Comp Neurol. 2007 Jan 10;500(2):311-21. PubMed.
  8. . Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease. Sci Transl Med. 2022 Oct 19;14(667):eabn9380. PubMed.
  9. . Differential effects of familial Alzheimer's disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity. Acta Neuropathol Commun. 2023 Jun 1;11(1):87. PubMed.
  10. . The amyloid precursor protein modulates the position and length of the axon initial segment offering a new perspective on Alzheimer's disease genetics. 2022 Jan 24 10.1101/2022.01.23.477413 (version 1) bioRxiv.
  11. . Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations. Cell Rep. 2016 Oct 11;17(3):759-773. PubMed.
  12. . Swedish Alzheimer's disease variant perturbs activity of retrograde molecular motors and causes widespread derangement of axonal transport pathways. J Biol Chem. 2024 Apr;300(4):107137. Epub 2024 Mar 5 PubMed.
  13. . The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway. Nat Med. 1995 Dec;1(12):1291-6. PubMed.
  14. . Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the "beta-secretase" site occurs in the golgi apparatus. J Biol Chem. 1996 Apr 19;271(16):9390-7. PubMed.
  15. . Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence. J Biol Chem. 2016 Nov 11;291(46):24041-24053. Epub 2016 Sep 29 PubMed.
  16. . 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.
  17. . The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.
  18. . 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.
  19. . 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.
  20. . 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.
  21. . 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.
  22. . Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993 Jan 22;259(5094):514-6. PubMed.
  23. . Aβ43 levels determine the onset of pathological amyloid deposition. J Biol Chem. 2023 Jul;299(7):104868. Epub 2023 May 29 PubMed.
  24. . A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019 Oct 23;104(2):256-270.e5. Epub 2019 Aug 12 PubMed.

Further Reading

Papers

  1. . Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease. Neurochem Res. 2021 Oct;46(10):2676-2686. Epub 2021 Mar 12 PubMed.

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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