Alzheimer's disease (AD) is the most common cause of dementia in humans. A 
pathological hallmark in the brain of an AD patient is extracellular amyloid 
plaques formed by accumulated beta-amyloid protein (Abeta), a metabolic product 
of amyloid precursor protein (APP). Studies have revealed a strong genetic 
linkage in the early-onset familial form (<60 years old) of AD. For example, 
some mutant APPs are transmitted dominantly and are segregated with inheritance 
of early onset AD. These mutants facilitate Abeta production. The "Swedish" 
mutations (APP(SW)) and the "London" mutation (APP(LON)) are examples of these 
mutants. Selective silencing of these mutant alleles holds therapeutic promise 
for AD. Here we show that the expression of the mutant APPs was selectively 
inhibited by RNA interference. The best selectivity was obtained when the 
mismatches were centrally placed in the antisense strand of small interfering 
RNAs. Introducing an additional mismatch in the antisense strand may improve the 
selectivity. The addition of a G at 5' end of the antisense strand may enhance 
the efficacy of gene silencing by RNA interference. Our results illustrate the 
guiding principles for selection of targeted sequences to achieve 
allele-specific silencing. The sequences that are effective to silence APP(SW) 
and APP(LON) as identified in this study may be useful in both in vivo and in 
vitro studies to investigate the pathophysiological role of APP(SW) and APP(LON) 
in AD development.