A majority of mutations within the amyloid β (Aβ) region of the amyloid precursor protein (APP) gene cause inherited forms of intracerebral haemorrhage. Most of these mutations may also cause cognitive impairment, but the Arctic APP mutation is the only known intra-Aβ mutation to date causing the more typical clinical picture of Alzheimer's disease (AD).
To describe features of one Swedish and one American family with the previously reported Arctic APP mutation.
Affected and non-affected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, one brain from each family was investigated neuropathologically.
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 AD and similar to the phenotype for other AD 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 and one American case with the Arctic APP mutation have come to autopsy, neither of which showed any signs of haemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathology as well as abundant amyloid plaques. Intriguingly, a majority of plaques from both of these cases had a characteristic ring-like character.
Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with AD.