Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease
Open accessAbstract
BACKGROUND: A majority of mutations within the beta-amyloid region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral hemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-beta-amyloid mutation to date causing the more typical clinical picture of Alzheimer disease. OBJECTIVE: To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation. DESIGN, SETTING, AND PARTICIPANTS: Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically. RESULTS: The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character. CONCLUSIONS: Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.
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To date, 228 PSEN1 mutations have been identified causing ADAD.
“To date, 228 PSEN1 mutations have been identified causing ADAD (49, 303, 304, 440, 566, 580).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [49]
The Introduction identifies PS1 (PSEN1) as a gene with AD-causing mutations, but says that about 150 PS1 mutations had been described, not 228. That is the count this 2008 paper gives; it cannot substantiate the citing sentence’s count of 228. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAPP mutations can lead to cerebrovascular pathology including BBB breakdown and cerebral amyloid angiopathy in humans and transgenic animal models expressing human APP mutations.
“APP mutations can lead to cerebrovascular pathology including BBB breakdown and cerebral amyloid angiopathy (CAA), as shown in humans (49, 211, 356, 674) and transgenic animal models expressing human APP mutations (56, 57, 137, 321, 322, 331, 336, 405, 420, 464, 467, 512, 513, 579, 606).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [49]
The Results and Discussion report severe amyloid angiopathy in human carriers of the Arctic APP mutation, supporting the cerebral amyloid angiopathy portion. Our copy does not report blood–brain barrier breakdown. The sentence cites other sources for the transgenic-animal portion. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIndividuals with vasculotropic APP mutations within Aβ 21-23 residues, including Dutch, Arctic, Flemish, Iowa, and Italian mutations, develop prominent CAA causing extensive cerebrovascular pathology.
“Individuals with 'vasculotropic' APP mutations within A 𝛃 21-23 residues including Dutch (E693Q), Arctic (E693G), Flemish (A692G), Iowa (D694N), and Italian (E693K) mutation (49, 211, 335, 356, 526, 674) develop prominent CAA (238, 640) causing extensive cerebrovascular pathology.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [49]
The Introduction (page unavailable) describes cerebral amyloid angiopathy and cerebrovascular injury in carriers of the Dutch, Flemish, and Iowa mutations. The Results report severe angiopathy in two Arctic cases, but the Discussion says no brain haemorrhage had been observed in Arctic carriers and emphasizes their different phenotype. The cited copy does not address the Italian mutation, so it does not support the claim for all five mutations. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCBF reductions have been reported in humans carrying vasculotropic APP mutations.
“CBF reductions have also been reported in humans carrying vasculotropic APP mutations (49).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [49]
Autosomal-dominant AD is caused by mutations in APP and PSEN1 and PSEN2 genes.
“Autosomal-dominant AD (ADAD) is an inherited form of AD caused by mutations in amyloid precursor protein ( APP ) and presenilin-1 and 2 ( PSEN1; PSEN2 ) genes (49, 177, 303, 304, 580).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [49]
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- Authors
- Basun, H., Bogdanovic, N., Ingelsson, M., Almkvist, O., Näslund, J., Axelman, K., Bird, T. D., Nochlin, D., Schellenberg, G. D., Wahlund, L.-O., & Lannfelt, L.
- Affiliations
- Karolinska Institutet (SE)
- Uppsala University (SE)
- Stockholm University (SE)
- University of Washington (US)
- ORCID
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2008-04-01
- Volume
- 65
- Issue
- 4
- Pages
- 499
- ISSN
- 0003-9942 (ISSN-L)
- PMC
- PMC2723757
- OpenAlex
- W2126866809
- Cited by
- 115
- References
- 26
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 4 · 2014: 10 · 2013: 6 · 2012: 10
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (P50AG005136)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- amyloid precursor protein, early-onset Alzheimer's disease, familial Alzheimer's disease, intracerebral hemorrhage, cognitive impairment, brain atrophy, cerebral amyloid angiopathy, neurofibrillary tangles, amyloid plaques, neuropathology
- MeSH terms
- Age Factors, Aged, Alzheimer Disease, Atrophy, Brain, Child, Electroencephalography, Female, Genotype, Genetic Carrier Screening, Humans, Magnetic Resonance Imaging, Middle Aged, Neurologic Examination, Neuropsychological Tests, Parietal Lobe, Pedigree, Phenotype, Receptors, Cell Surface, Regional Blood Flow, Sweden, United States, Tomography, Emission-Computed, Single-Photon, Amyloid beta-Protein Precursor, Age of Onset, Plaque, Amyloid, Protease Nexins
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