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APP mutations
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The APP gene is located on chromosome 21q21 (Korenberg et al 1989 and it was the first Alzheimer’s gene to be discovered. Analysis of chromosome 21 followed on from observations that Down’s syndrome patients, who have three copies of chromosome 21, develop AD in their forties. It was identified as a gene for familial early-onset Alzheimer's disease (EOAD) when a missense mutation, the so-called London mutation V717I, was shown to segregate within a single kindred in which AD had been confirmed by autopsy (Goate et al 1991 Approximately 15 disease-causing mutations have been identified in APP, and these account for a small proportion of familial EOAD (~5%). Patients with APP mutations generally develop disease symptoms from 40 to 60 years of age. APP mutations are located in exons 16 and 17, where they cluster primarily around the secretase processing sites.

FAD mutations in APP either increase production of both Aβ peptides or specifically elevate Aβ42 (Haass et al 1994 Citron et al 1992 Cai et al 1993 Mutations near the β-secretase site augment β-secretase cleavage and increase general Aβ levels, whereas mutations near the γ-secretase site specifically increase Aβ42. Some FAD mutations also affect AICD production but this does not correlate with an increase or decrease in Aβ levels (Hecimovic et al 2004 indicating that FAD mutations exert their pathogenic effect by altering Aβ processing and not APP signalling. Mutations in APP are also associated with an increased risk of cerebral amyloid angiopathy (CAA). In addition to coding variants, APP promoter polymorphisms are possible susceptibility factors for AD (Wavrant-DeVrieze et al 1999

See also the APP mutations directory on the Alzheimer Research Forum website

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APP mutations