Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr21:25891855 A>G
Position: (GRCh37/hg19):Chr21:27264167 A>G
dbSNP ID: rs63751039
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GGA
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 9

Findings

This mutation was identified in a four-generation family from northern Sweden. Affected individuals presented with clinical features of early onset Alzheimer's disease with a mean age of onset of 57 ± 2.9 years and insidious cognitive decline (Nilsberth et al., 2001). The mutation was shown to cosegregate with disease. The mutation was also reported in an individual of Swedish origin living in the United States who is thought to be a member of the same kindred (Kamino et al., 1992). Plasma levels of both Aβ42 and Aβ40 were lower in mutation carriers than in healthy family members (Nilsberth et al., 2001). A subsequent study reported additional clinical and neuropathological characteristics of carriers in both families (Basun et al., 2008).

This mutation is sometimes called "E22G" because it affects the twenty-second amino acid of Aβ peptides.

The mutation was absent from the gnomAD variant database (V2.1.1, Oct 2021).

Neuropathology

Neuropathological assessments of several mutation carriers showed neuritic plaques and neurofibrillary tangles consistent with a diagnosis of AD (Kamino et al., 1992, Basun et al., 2008, Philipson et al., 2012, Kalimo et al., 2013). The deposition of different Aβ peptides is highly variable across different brain regions, with cerebral cortical plaques frequently having a “targetoid” shape with N- and C-truncated Aβ peptides of different sizes in the center surrounded by coronas of Aβ42.  Consistent with earlier brain imaging studies (Nilsberth et al., 2001), autopsies of at least two carriers showed no signs of hemorrhage, but revealed severe congophilic angiopathy.

Interestingly, cortical PiB retention, a marker of amyloid fibrils, was very low in two Arctic mutation carriers compared with both noncarrier siblings and two individuals with other pathogenic mutations (APP Swedish and PSEN1 H163Y). Cerebral glucose metabolism was abnormal in all mutation carriers, as were CSF levels of Aβ(1-42), total tau, and phosphorylated tau (Schöll et al., 2012). A subsequent study confirmed the very low binding of PiB as assessed by autoradiography of postmortem brain sections, and revealed a positive correlation between tau deposition and astrocyte activation that was not observed in brain tissues from patients with sporadic AD or a PSEN1 ΔE9 mutation (Lemoine et al., 2021).

MRI and SPECT imaging revealed general brain atrophy and reduced blood flow of the parietal lobe in several affected mutation carriers (Basun et al., 2008).

Biological Effect

E22G toxicity has been reported in multiple experimental systems, including human neuroblastoma cells (Perálvarez-Marín et al., 2009) and mouse hippocampal slices in which extracellular mutant Aβ40, and particularly Aβ2, caused dendritic spine loss and an increase in tau phosphorylation and tau-dependent neurodegeneration (Tackenberg et al., 2020). Also, E22G Aβ40 blocked LTP in wildtype mice and transgenic mice expressing the human APP with the Arctic mutation developed amyloid deposits in the brain and deficits in learning and memory (Rönnbäck et al., 2011) with learning impairment correlating with protofibril levels (Lord et al., 2009).  However, synaptogenesis, as assessed by synaptophysin staining, was unaffected by E693G expression in primary cortical neurons (Schilling et al., 2023). Also, cellular localization to the cis-Golgi and early endosomes was similar to wildtype APP.

Arctic Aβ40 has an increased propensity to form protofibrils and does so at a faster rate compared with wild-type Aβ40 (Nilsberth et al., 2001, Aug 2001 news). Consistent with these findings, subsequent studies described the formation of large oligomers and abundant amyloid fibrils without a detectable aggregation lag phase (Bitan et al., 2003, Hatami et al., 2017, Yang et al., 2018, Illes-Toth et al., 2021, Seuma et al., 2022). Of note, Nilsberth's and colleagues' initial discovery contributed to the development of the FDA-approved antibody lecanemab/Leqembi which selectively binds to large, soluble Aβ protofibrils.

Spectrometry and protein modeling studies have shown that, although E22G monomers appear structurally similar to wildtype and other mutant monomers, E22G oligomers, protofibrils, and protofilaments are structurally unique (Gessel et al., 2012, Fawzi et al., 2008). One spectroscopic study reported E22G peptides as a mixture of mostly disordered and α-helical structures with low β-sheet content (Perálvarez-Marín et al., 2009). Another reported the substitution reduced the propensity to form α-helical structures and lowered conformational stability, while facilitating β-strand conversion and increasing fibril nucleation rates (Lo et al., 2015). Consistent with these observations, adding mutations that stabilize α-helical structure decreased E22G aggregation and cytotoxicity (Chen et al., 2013). Also, molecular dynamics simulations predicted E22G destabilizes α-helix structure, likely increasing solvent exposure which may fuel fibril formation (Hayward and Kitao 2021, Davidson et al., 2022). A study of the kinetics of E22G aggregation suggested that acceleration of this process stems primarily from an enhancement of secondary nucleation on the surface of existing fibrils (Yang et al., 2018). The smaller size of the side-chain at position 22 resulting from the E to G substitution was proposed as having a drastic effect on aggregation propensity.

In contrast to mutant Aβ40, mutant Aβ42 appears to form monomorphic, rather than polymorphic, fibrils, with a core structure similar to that of wildtype Aβ42. Cryo-EM structures of E22G from human brain revealed subtle conformational changes in the peptide folds compared with wild-type Aβ42 filaments. The authors hypothesized these changes were due to the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation (Yang et al., 2023; see also the Amyloid Atlas, May 2023 news). A high-resolution characterization of Aβ42 fibrils generated from bacterial-synthesized protein was consistent with these findings (Golota et al., 2024). Of note, filaments extracted from the brains of APP^NL-G-F knockin mice shared some similarities with the human filaments, but were not identical. A study of the architecture of Aβ plaques in the brains of these mice revealed a paired, S-shaped protofilament core of Aβ42 fibrils with the substituted G22 deeply buried within the fibril, and with abundant remnants of subcellular components intermixed (Leistner et al., 2023, May 2023 news). Interestingly, several forms of amyloid were observed, but they did not match the originally predicted protofibril structure (Nilsberth et al., 2001).

Also of note, an in vitro study suggested that wildtype Aβ42 seeds enhance misfolding of E22G, but not wildtype, Aβ40 (Yoo et al., 2018). This prion-like crosstalk, which could occur in heterozygote carriers, may accelerate amyloid pathology.

A few studies have suggested E22Q may insert into cell membranes and cause cytotoxicity. One in vitro study, for example, indicated E22Q trimers and/or hexamers destabilize membranes and disrupt their integrity (McKnelly et al., 2022). Similarly, a structural modeling study predicted that E22G partitions into the membrane more than wild type Aβ and suggested this may disrupt the normal function of these peptides in the endosomal lumen where they have been proposed to play important roles in synaptic and neuronal function (Kim and Bezprozvanny, 2023). Also of note, E693 lies within a cholesterol-binding site as determined by NMR resonance spectroscopy and site-directed mutagenesis (Barrett et al., 2012).

E22G also appears to differ from wildtype Aβ in its production and clearance. The effects of E693G on Aβ40 and Aβ42 production have varied between studies. In conditioned media from cultured cells, the mutation was first reported to diminished Aβ42 while minimally affecting Aβ40 levels resulting in a decreased Aβ42/Aβ40 ratio (Nilsberth et al., 2001). In a subsequent study of cells expressing the Arctic and Swedish mutations together, both Aβ40 and Aβ42 levels  were reduced in conditioned media from transfected cells (Stenh et al., 2002), mirroring the reductions seen in carrier plasma (Nilsberth et al., 2001).

A more detailed examination of the multiple peptides resulting from APP processing found neither Aβ40 nor Aβ42 production changed compared with wildtype APP (Schilling et al., 2023). However, this latter study found increased production of N-terminally truncated Aβ peptides starting at position 5: Aβ5-29 and Aβ5-33. This is in contrast to wildtype APP, where mainly Aβ5-40 was identified. The authors suggested the mutant C-terminally shortened peptides might contribute to AD progression. Also of note, E693G was one of several pathogenic APP mutations found to confer resistance to neprilysin-catalyzed proteolysis of Aβ40 (Tsubuki et al., 2003).

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

Multiple rodent models carrying the Arctic mutation have been generated. The TgAPParc model, for example, is a transgenic mouse with human APP bearing the mutation. Most others, including transgenic and knockin models, carry additional APP mutations, such as APP NL-G-F Knock-in, AppSAA Knock-in, Arc48 (APPSw/Ind/Arc), ArcAβ, and Tg-ArcSwe mice, as well as the App NL-G-F Knock-in Rat.

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References

Research Models Citations

1. TgAPParc
2. APP NL-G-F Knock-in
3. AppSAA Knock-in
4. Arc48 (APPSw/Ind/Arc)
5. ArcAβ
6. Tg-ArcSwe
7. App NL-G-F Knock-in Rat

Mutations Citations

1. PSEN1 S290_S319delinsC (ΔE9Finn)

News Citations

1. "Arctic" APP Mutation Supports Protofibril Role 22 Nov 2002
2. Amyloid Atlas Showcases 261 Structures, and Counting 11 May 2023
3. Amyloid Jungle: Plaque Fibrils Mesh With All Manner of Vesicles, Membranes 24 May 2023

Therapeutics Citations

1. Leqembi

Paper Citations

1. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Näslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.
2. Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM, Anderson L, O'dahl S, Nemens E, White JA. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet. 1992 Nov;51(5):998-1014. PubMed.
3. Basun H, Bogdanovic N, Ingelsson M, Almkvist O, Näslund J, Axelman K, Bird TD, Nochlin D, Schellenberg GD, Wahlund LO, Lannfelt L. Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol. 2008 Apr;65(4):499-505. PubMed.
4. Philipson O, Lord A, Lalowski M, Soliymani R, Baumann M, Thyberg J, Bogdanovic N, Olofsson T, Tjernberg LO, Ingelsson M, Lannfelt L, Kalimo H, Nilsson LN. The Arctic amyloid-β precursor protein (AβPP) mutation results in distinct plaques and accumulation of N- and C-truncated Aβ. Neurobiol Aging. 2012 May;33(5):1010.e1-13. Epub 2011 Nov 26 PubMed.
5. Kalimo H, Lalowski M, Bogdanovic N, Philipson O, Bird TD, Nochlin D, Schellenberg GD, Brundin R, Olofsson T, Soliymani R, Baumann M, Wirths O, Bayer TA, Nilsson LN, Basun H, Lannfelt L, Ingelsson M. The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ. Acta Neuropathol Commun. 2013 Sep 10;1:60. PubMed.
6. Schöll M, Wall A, Thordardottir S, Ferreira D, Bogdanovic N, Långström B, Almkvist O, Graff C, Nordberg A. Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers. Neurology. 2012 Jul 17;79(3):229-36. PubMed.
7. Lemoine L, Gillberg PG, Bogdanovic N, Nennesmo I, Saint-Aubert L, Viitanen M, Graff C, Ingelsson M, Nordberg A. Amyloid, tau, and astrocyte pathology in autosomal-dominant Alzheimer's disease variants: AβPParc and PSEN1DE9. Mol Psychiatry. 2021 Oct;26(10):5609-5619. Epub 2020 Jun 25 PubMed.
8. Perálvarez-Marín A, Mateos L, Zhang C, Singh S, Cedazo-Mínguez A, Visa N, Morozova-Roche L, Gräslund A, Barth A. Influence of residue 22 on the folding, aggregation profile, and toxicity of the Alzheimer's amyloid beta peptide. Biophys J. 2009 Jul 8;97(1):277-85. PubMed.
9. Tackenberg C, Kulic L, Nitsch RM. Familial Alzheimer's disease mutations at position 22 of the amyloid β-peptide sequence differentially affect synaptic loss, tau phosphorylation and neuronal cell death in an ex vivo system. PLoS One. 2020;15(9):e0239584. Epub 2020 Sep 23 PubMed.
10. Rönnbäck A, Sagelius H, Bergstedt KD, Näslund J, Westermark GT, Winblad B, Graff C. Amyloid neuropathology in the single Arctic APP transgenic model affects interconnected brain regions. Neurobiol Aging. 2011 Aug 29; PubMed.
11. Lord A, Englund H, Söderberg L, Tucker S, Clausen F, Hillered L, Gordon M, Morgan D, Lannfelt L, Pettersson FE, Nilsson LN. Amyloid-beta protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice. FEBS J. 2009 Feb;276(4):995-1006. PubMed.
12. 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.
13. Bitan G, Vollers SS, Teplow DB. Elucidation of primary structure elements controlling early amyloid beta-protein oligomerization. J Biol Chem. 2003 Sep 12;278(37):34882-9. Epub 2003 Jul 2 PubMed.
14. Hatami A, Monjazeb S, Milton S, Glabe CG. Familial Alzheimer's Disease Mutations within the Amyloid Precursor Protein Alter the Aggregation and Conformation of the Amyloid-β Peptide. J Biol Chem. 2017 Feb 24;292(8):3172-3185. Epub 2017 Jan 3 PubMed.
15. Yang X, Meisl G, Frohm B, Thulin E, Knowles TP, Linse S. On the role of sidechain size and charge in the aggregation of Aβ42 with familial mutations. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E5849-E5858. Epub 2018 Jun 12 PubMed.
16. Illes-Toth E, Meisl G, Rempel DL, Knowles TP, Gross ML. Pulsed Hydrogen-Deuterium Exchange Reveals Altered Structures and Mechanisms in the Aggregation of Familial Alzheimer's Disease Mutants. ACS Chem Neurosci. 2021 Jun 2;12(11):1972-1982. Epub 2021 May 14 PubMed.
17. Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022 Nov 18;13(1):7084. PubMed.
18. Gessel MM, Bernstein S, Kemper M, Teplow DB, Bowers MT. Familial Alzheimer's disease mutations differentially alter amyloid β-protein oligomerization. ACS Chem Neurosci. 2012 Nov 21;3(11):909-18. Epub 2012 Jun 26 PubMed.
19. Fawzi NL, Kohlstedt KL, Okabe Y, Head-Gordon T. Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide. Biophys J. 2008 Mar 15;94(6):2007-16. Epub 2007 Nov 21 PubMed.
20. Lo CJ, Wang CC, Huang HB, Chang CF, Shiao MS, Chen YC, Lin TH. The Arctic mutation accelerates Aβ aggregation in SDS through reducing the helical propensity of residues 15-25. Amyloid. 2015 Mar;22(1):8-18. Epub 2014 Nov 7 PubMed.
21. Chen YR, Huang HB, Lo CJ, Wang CC, Ho LK, Liu HT, Shiao MS, Lin TH, Chen YC. Effect of alanine replacement of l17 and f19 on the aggregation and neurotoxicity of arctic-type aβ40. PLoS One. 2013;8(4):e61874. Print 2013 PubMed.
22. Hayward S, Kitao A. The role of the half-turn in determining structures of Alzheimer's Aβ wild-type and mutants. J Struct Biol. 2021 Dec;213(4):107792. Epub 2021 Sep 2 PubMed.
23. Davidson DS, Kraus JA, Montgomery JM, Lemkul JA. Effects of Familial Alzheimer's Disease Mutations on the Folding Free Energy and Dipole-Dipole Interactions of the Amyloid β-Peptide. J Phys Chem B. 2022 Oct 6;126(39):7552-7566. Epub 2022 Sep 23 PubMed.
24. Yang Y, Zhang W, Murzin AG, Schweighauser M, Huang M, Lövestam S, Peak-Chew SY, Saito T, Saido TC, Macdonald J, Lavenir I, Ghetti B, Graff C, Kumar A, Nordberg A, Goedert M, Scheres SH. Cryo-EM structures of amyloid-β filaments with the Arctic mutation (E22G) from human and mouse brains. Acta Neuropathol. 2023 Mar;145(3):325-333. Epub 2023 Jan 7 PubMed.
25. Golota NC, Michael B, Saliba EP, Linse S, Griffin RG. Structural characterization of E22G Aβ1-42 fibrils via1H detected MAS NMR. Phys Chem Chem Phys. 2024 May 22;26(20):14664-14674. PubMed.
26. Leistner C, Wilkinson M, Burgess A, Lovatt M, Goodbody S, Xu Y, Deuchars S, Radford SE, Ranson NA, Frank RA. The in-tissue molecular architecture of β-amyloid pathology in the mammalian brain. Nat Commun. 2023 May 17;14(1):2833. PubMed.
27. Yoo BK, Xiao Y, McElheny D, Ishii Y. E22G Pathogenic Mutation of β-Amyloid (Aβ) Enhances Misfolding of Aβ40 by Unexpected Prion-like Cross Talk between Aβ42 and Aβ40. J Am Chem Soc. 2018 Feb 28;140(8):2781-2784. Epub 2018 Feb 20 PubMed.
28. McKnelly KJ, Kreutzer AG, Howitz WJ, Haduong K, Yoo S, Hart C, Nowick JS. Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ16-36. Biochemistry. 2022 Mar 15;61(6):446-454. Epub 2022 Feb 25 PubMed.
29. Kim M, Bezprozvanny I. Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease. Int J Mol Sci. 2023 Jan 20;24(3) PubMed.
30. Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science. 2012 Jun 1;336(6085):1168-71. PubMed.
31. Stenh C, Nilsberth C, Hammarbäck J, Engvall B, Näslund J, Lannfelt L. The Arctic mutation interferes with processing of the amyloid precursor protein. Neuroreport. 2002 Oct 28;13(15):1857-60. PubMed.
32. Tsubuki S, Takaki Y, Saido TC. Dutch, Flemish, Italian, and Arctic mutations of APP and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet. 2003 Jun 7;361(9373):1957-8. PubMed.

Other Citations

1. APP Swedish

External Citations

1. Amyloid Atlas

Further Reading