The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation
Abstract
Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta-protein (Abeta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the Abeta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased Abeta42 and Abeta40 levels in plasma. Additionally, low levels of Abeta42 were detected in conditioned media from cells transfected with APPE693G. Fibrillization studies demonstrated no difference in fibrillization rate, but Abeta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) Abeta. The finding of increased protofibril formation and decreased Abeta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid Abeta protofibril formation leading to accelerated buildup of insoluble Abeta intra- and/or extracellularly.
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In Scarlet Road, the top gantenerumab dose of 225 mg produced only a 4.8% reduction in amyloid-beta from baseline, about 3 centiloids.
“at the top dose of 225 mg, there was only a 4.8% reduction in levels of Aβ from baseline (~3 CL)”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [64]
Other Aβ forms besides fibrils and plaques may trigger brain toxicity and contribute to AD synaptic failure.
“These findings indicated that other forms of Aβ, besides fibrils and plaques, may trigger brain toxicity and contribute to AD-synaptic failure (115,116,118,119).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [115]
The human APP Arctic and E693Δ (Osaka) mutations show an AD type with low cerebral plaque deposition, modest Aβ-PET binding, and higher production of oligomers and protofibrils likely to initiate Aβ toxicity.
“The recently discovered human APP Arctic (115) and E693Δ (Osaka) (116) mutations show a type of AD with low cerebral deposition of plaques, as indicated by modest Aβ-positron emission tomography radiotracer binding (117) and higher production of oligomers and protofibrils that are likely to be the initiators of Aβ toxicity (115,116,118,119).”
From The β-Secretase BACE1 in Alzheimer’s Disease (2021) · cites this paper as [115]
The Arctic FAD mutation within the mid-region of Aβ primarily increases the propensity for Aβ aggregation rather than secretion.
“The Arctic FAD mutation within the mid-region of Aβ [133] primarily increase the propensity for Aβ aggregation rather than secretion.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [133]
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- Authors
- Nilsberth, C., Westlind-Danielsson, A., Eckman, C. B., Condron, M. M., Axelman, K., Forsell, C., Stenh, C., Luthman, J., Teplow, D. B., Younkin, S. G., Näslund, J., & Lannfelt, L.
- Affiliations
- Karolinska Institutet (SE)
- Mayo Clinic (US)
- Brigham and Women's Hospital (US)
- AstraZeneca (Sweden) (SE)
- Corresponding author
- Lannfelt, Lars
- Venue
- Nature Neuroscience
- Published
- 2001-08-20
- Volume
- 4
- Issue
- 9
- Pages
- 887-893
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2029695041
- Cited by
- 1,209
- References
- 40
- Citations by year
- 2026: 28 · 2025: 46 · 2024: 60 · 2023: 53 · 2022: 54 · 2021: 61 · 2020: 59 · 2019: 48 · 2018: 52 · 2017: 50 · 2016: 42 · 2015: 45 · 2014: 56 · 2013: 59 · 2012: 51
- FWCI
- 23.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5p01ag014366-05)
- National Institute on Aging (AG14366)
- National Institute of Neurological Disorders and Stroke (R01NS038328, NS38328)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid precursor protein, Arctic mutation, amyloid-beta, amyloid-beta 42, Aβ40, amyloid fibril formation, familial Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Cell Line, Culture Media, Heterozygote, Humans, Middle Aged, Mutation, Pedigree, Peptide Fragments, Sweden, Amyloid beta-Peptides, Amyloid beta-Protein Precursor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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