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. 2008 Apr;65(4):499-505.
doi: 10.1001/archneur.65.4.499.

Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease

Hans Basun  1 , Nenad Bogdanovic, Martin Ingelsson, Ove Almkvist, Jan Näslund, Karin Axelman, Thomas D Bird, David Nochlin, Gerard D Schellenberg, Lars-Olof Wahlund, Lars Lannfelt
Affiliations

Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease

Hans Basun et al. Arch Neurol. 2008 Apr.

Abstract

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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Figures

Fig. 1
Fig. 1
a) Pedigree of the Swedish family with the Arctic APP mutation. b) Pedigree of the American family with the Arctic APP mutation. Generations are marked with roman and certain individuals with greek numbers, which refer to those given in the text.
Fig. 1
Fig. 1
a) Pedigree of the Swedish family with the Arctic APP mutation. b) Pedigree of the American family with the Arctic APP mutation. Generations are marked with roman and certain individuals with greek numbers, which refer to those given in the text.
Fig. 2
Fig. 2
Immunohistochemistry by the Aβ x-42 mAb on tissue from frontal neocortex of the Swedish (a) and the American (b) Arctic APP mutation case. Note that the amyloid pathology is spread throughout the cortical thickness. Also, for both cases, the amyloid plaques have a characteristic non-cored ring form (a and b inserts). Size bars= 250 μm and 50 μm (inserts).
Fig. 3
Fig. 3
Bielschowsky silver impregnation staining indicate neuritic features of the ring-formed plaques in the Swedish (a) and American (b) Arctic APP mutation case. c) Only arteries (thick arrow) were stained with Congo Red, demonstrating congophilic angiopathy. The ring-formed plaques (thin arrows) were negative for Congo Red. Size Bars = 50μm.
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