A novel presenilin 1 mutation insR352 associated with a frontal temporal dementia phenotype has been identified (E. A. Rogaeva et al. 2001 Neurology 57 621-625). This mutation does not increase Aβ42 levels but instead acts as dominant negative presenilin decreasing amyloid β protein (Aβ) production by inhibiting γ-secretase cleavage of the Aβ precursor. The distinct clinical phenotype associated with this mutation suggests that chronic partial inhibition of γ-secretase activity may result in neurodegeneration.
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