Responsiveness to cholinesterase inhibitors in Alzheimer's disease: a possible role for the 192 Q/R polymorphism of the PON-1 gene.
Cholinesterase inhibitors (ChEIs) are the most established treatment strategy in Alzheimer's disease (AD). However, the responsiveness to these drugs is widely heterogeneous and the majority of AD subjects do not respond to treatment. Paraoxonase-1 (PON-1) is a potent endogenous ChEI and has been widely studied for its ability to hydrolyze environmental neurotoxins. Serum levels and biological activity of PON-1 display wide inter-individual variability and are strongly influenced by a common polymorphism at position 192 of the PON-1 gene. Here, we evaluated whether this gene variation is associated with differences in the ability of AD subjects to respond to therapy with ChEIs. We found that individuals that respond to ChEIs had a significantly higher frequency of the R allele, compared to non-responders (P<0.05). This study indicates that the 192 Q/R polymorphism of the PON-1 gene might influence responsiveness to ChEIs, with potentially important implications for the treatment of AD. Mutations of genes encoding for endogenous modulators of the cholinergic system should merit further investigation as prognostic indicators of individual response to treatment in AD subjects.
Pola
Roberto
R
Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, L.go A. Gemelli 8, 00168 Rome, Italy. rob_pola@hotmail.com
Flex
Andrea
A
Ciaburri
Michele
M
Rovella
Emilio
E
Valiani
Angela
A
Reali
Giada
G
Silveri
Maria C
MC
Bernabei
Roberto
R
D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000235:genetics*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D016896:Treatment Outcome
D002800:Cholinesterase Inhibitors; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human