Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease | Cerebrovascular Disease | JAMA Neurology | JAMA Network
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Original Contribution
April 2008

Clinical and Neuropathological Features of the Arctic APP Gene Mutation Causing Early-Onset Alzheimer Disease

Author Affiliations

Author Affiliations: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden (Drs Basun, Bogdanovic, Almkvist, Näslund, and Wahlund and Ms Axelman); Rudbeck Laboratory, Division of Molecular Geriatrics, Department of Public Health, Uppsala University, Uppsala, Sweden (Drs Basun, Ingelsson, and Lannfelt); Department of Psychology, Stockholm University, Stockholm, Sweden (Dr Almkvist); and Departments of Neurology, Medicine, and Pathology, University of Washington and VA Geriatrics Research Center, Seattle (Drs Bird, Nochlin, and Schellenberg).

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

Background  A majority of mutations within the β-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–β-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.