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This is a mutation very close to the APP β-secretase cleavage site. The pathogenicity of Aβ42 Icelandic mutation A2T is lower than the native sequence. The precursor APP A673T is the first variant of APP found to reduce the risk of Alzheimer's disease in humans. A2T also affects the cleavage of γ-secretase, and the mutant is an inefficient substrate in a cell-based enzyme assay.