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


METHODS
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.
Basun
Hans
H
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden. hans.basun@pubcare.uu.se
Bogdanovic
Nenad
N
Ingelsson
Martin
M
Almkvist
Ove
O
Näslund
Jan
J
Axelman
Karin
K
Bird
Thomas D
TD
Nochlin
David
D
Schellenberg
Gerard D
GD
Wahlund
Lars-Olof
LO
Lannfelt
Lars
L
D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D002648:Child; D004569:Electroencephalography; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009460:Neurologic Examination; D009483:Neuropsychological Tests; D010296:Parietal Lobe / Q000098:blood supply / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D058225:Plaque, Amyloid / Q000473:pathology; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics*; D012039:Regional Blood Flow / Q000502:physiology; D013548:Sweden; D015899:Tomography, Emission-Computed, Single-Photon; D014481:United States
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface