Novel amyloid precursor protein mutation, Val669Leu ("Seoul APP"), in a Korean patient with early-onset Alzheimer's disease.

In this study, a novel mutation in APP gene, Val669Leu ("Seoul APP"), was reported in a Korean female patient with Alzheimer's disease. She developed cognitive decline at 56 years of age, and her memory declined rapidly over one-year period from her 1st visit to the hospital. Her Mini-Mental State Examination scores dropped from 25/30 to 13/30. Two years later, she developed parkinsonian features, myoclonic jerk, and generalized seizure. As the disease progressed, aggravated diffuse brain atrophy and small-vessel ischemic lesion was also observed, and she became mute and vegetative in 4 years from the symptom onset. Magnetic resonance imaging showed mild medial temporal lobe and hippocampal atrophy, and 18F-fluoro-deoxyglucose positron emission tomography showed bilateral temporoparietal hypometabolism. Plasma amyloid oligomer analysis revealed highly elevated Aβ oligomers levels in the proband patient. Family history revealed positive without biochemical confirmation because family members testified similar type of cognitive decline from the proband's mother and one of her aunt/uncle. Her half-siblings did not present any signs of memory impairment. Sanger sequencing of the proband patient revealed a novel mutation in APP gene, Val669Leu, but mutation was not found in her unaffected half-sisters. A designed algorithm by Guerreiro et al. on early-onset Alzheimer's disease-associated mutations suggested the mutation as possibly pathogenic mutation. On the other hand, PolyPhen2 and SIFT tools suggested as otherwise. Since the mutation was located nearby the β-secretase cleavage site of APP, right next to the Swedish APP (Lys,Met670/671Asn,Leu) mutation, it was named as "Seoul APP" mutation. 3D modeling revealed that this mutation could result in significant changes in loop orientation of APP and also its intramolecular interactions. Hence, a novel APP Val669Leu mutation could alter the binding interactions between APP and β-secretase, which may influence the Aβ40 and Aβ42 generations.