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Alzheimer dementia caused by a novel mutation located in the APP C‐terminal intracytosolic fragment

Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early‐onset AD mutations alter processing of APP increasing relative levels of Aβ42 peptide, either by increasing Aβ42 or decreasing Aβ40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early‐onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the ε‐cleavage site of APP and is the furthermost C‐terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Aβ42 and a decrease in Aβ40 levels resulting in a near three‐fold increase of the Aβ42/Aβ40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease. Hum Mutat 27(9), 888–896, 2006. © 2006 Wiley‐Liss, Inc.