Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP1, PP3, BS1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25897627 G>T
Position: (GRCh37/hg19):Chr21:27269939 G>T
Position: (GRCh38/hg38):Chr21:25897626 A>C
Position: (GRCh37/hg19):Chr21:27269938 A>C
dbSNP ID: rs63751263
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

Effects on APP processing

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), 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 (CTFs) which resulted in enlarged endosomes (Kwart et al., 2019, Aug 2019 news). CTF accumulation has also been reported in cells treated with conditioned media from mutant iPSC-derived neurons, a finding used to support the hypothesis that Aβ42 exerts product feedback inhibition on γ-secretases (Zoltowska et al., 2024).

Altered subcellular trafficking may contribute to disruptions in APP processing. While the major site for APP processing is thought to be early endosomes in the endocytic pathway, APP carrying the Swedish mutation was found to be predominantly processed in Golgi-derived vesicles of the secretory pathway (Haass 1995, Thinakaran 1996). Some recent studies have confirmed this alteration and extended the early findings. For example, Wang and colleagues found that mutant APP spent more time in the Golgi than wildtype APP and this was associated with enhanced amyloidogenic processing and Aβ secretion (Wang et al., 2024). However, another recent study failed to detect an effect of the mutation on subcellular localization (Schilling et al., 2023).

Effects on cellular functions

The Swedish mutation has been associated with several disruptions of neuronal function at the cellular level. In addition to alterations in the site of APP processing, mutant iPSC-derived neurons 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). Moreover, 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).

Metabolic abnormalities have also been detected. In iPSC-derived astrocytes and neurons, for example, elevated glycolytic and oxidative metabolism were reported, as well as altered glutamate synthesis and transport (Salcedo et al., 2023). In another study using iPSC-derived neurons, no effects on mitochondrial dynamics were detected, however, and only modest bioenergetic alterations were observed (MacMullen et al., 2024 preprint).

In vivo effects

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 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.

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). 

Human induced pluripotent stem cells (iPSCs) have also been generated. For example, in one case, CRISPR-Cas9 was used to introduce the Swedish mutation in an iPSC line derived from a skin biopsy from a healthy person (Frederiksen et al., 2019). These cells have been differentiated into neurons and astrocytes (Salcedo et al., 2023).

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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 30 Dec 2021
2. Familial AD Mutations, β-CTF, Spell Trouble for Endosomes 16 Aug 2019
3. Cholesterol Trafficking Takes a Hit in Alzheimer’s Neurons 28 Oct 2016
4. In Cultured Human Neurons, Aβ Spurs Synapse Growth 22 Oct 2022

Paper Citations

1. Duan Y, Ye T, Qu Z, Chen Y, Miranda A, Zhou X, Lok KC, Chen Y, Fu AK, Gradinaru V, Ip NY. 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. Frederiksen HR, Holst B, Ramakrishna S, Muddashetty R, Schmid B, Freude K. Generation of two iPSC lines with either a heterozygous V717I or a heterozygous KM670/671NL mutation in the APP gene. Stem Cell Res. 2019 Jan;34:101368. Epub 2018 Dec 24 PubMed.
3. Salcedo C, Pozo Garcia V, García-Adán B, Ameen AO, Gegelashvili G, Waagepetersen HS, Freude KK, Aldana BI. Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease. J Neurochem. 2024 May;168(5):822-840. Epub 2023 Dec 8 PubMed.
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9. Schilling S, Pradhan A, Heesch A, Helbig A, Blennow K, Koch C, Bertgen L, Koo EH, Brinkmalm G, Zetterberg H, Kins S, Eggert S. 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.
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16. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. 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.
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20. Zoltowska KM, Das U, Lismont S, Enzlein T, Maesako M, Houser MC, Franco ML, Özcan B, Gomes Moreira D, Karachentsev D, Becker A, Hopf C, Vilar M, Berezovska O, Mobley W, Chávez-Gutiérrez L. Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling. Elife. 2024 Jul 19;12 PubMed.
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22. Thinakaran G, Teplow DB, Siman R, Greenberg B, Sisodia SS. 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.
23. Wang J, Gleeson PA, Fourriere L. Spatial-Temporal Mapping Reveals the Golgi as the Major Processing Site for the Pathogenic Swedish APP Mutation: Familial APP Mutant Shifts the Major APP Processing Site. Traffic. 2024 Mar;25(3):e12932. PubMed.
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30. Zhou B, Lu JG, Siddu A, Wernig M, Südhof TC. Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease. Sci Transl Med. 2022 Oct 19;14(667):eabn9380. PubMed.

Further Reading