Pharmacogenomics and therapeutic prospects in dementia.
Dementia is a major problem of health in developed countries. Alzheimer's disease (AD) is the main cause of dementia, accounting for 50-70% of the cases, followed by vascular dementia (30-40%) and mixed dementia (15-20%). Approximately 10-15% of direct costs in dementia are attributed to pharmacological treatment, and only 10-20% of the patients are moderate responders to conventional anti-dementia drugs, with questionable cost-effectiveness. Primary pathogenic events underlying the dementia process include genetic factors in which more than 200 different genes distributed across the human genome are involved, accompanied by progressive cerebrovascular dysfunction and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PS1, PS2) are only present in less than 5% of the AD population; however, the presence of the APOE-4 allele in the apolipoprotein E (APOE) gene represents a major risk factor for more than 40% of patients with dementia. Genotype-phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci (APP, PS1, PS2) and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for 20-95% of variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in AD is genotype-specific depending upon genes associated with AD pathogenesis and/or genes responsible for drug metabolism (CYPs). In monogenic-related studies, APOE-4/4 carriers are the worst responders. In trigenic (APOE-PS1-PS2 clusters)-related studies the best responders are those patients carrying the 331222-, 341122-, 341222-, and 441112- genomic profiles. The worst responders in all genomic clusters are patients with the 441122+ genotype, indicating the powerful, deleterious effect of the APOE-4/4 genotype on therapeutics in networking activity with other AD-related genes. Cholinesterase inhibitors of current use in AD are metabolized via CYP-related enzymes. These drugs can interact with many other drugs which are substrates, inhibitors or inducers of the cytochrome P-450 system; this interaction elicits liver toxicity and other adverse drug reactions. CYP2D6-related enzymes are involved in the metabolism of more than 20% of CNS drugs. The distribution of the CYP2D6 genotypes differentiates four major categories of CYP2D6-related metabolyzer types: (a) Extensive Metabolizers (EM)(*1/*1, *1/*10)(51.61%); (b) Intermediate Metabolizers (IM) (*1/*3, *1/*4, *1/*5, *1/*6, *1/*7, *10/*10, *4/*10, *6/*10, *7/*10) (32.26%); (c) Poor Metabolizers (PM) (*4/*4, *5/*5) (9.03%); and (d) Ultra-rapid Metabolizers (UM) (*1xN/*1, *1xN/*4, Dupl) (7.10%). PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacological treatments in AD. It seems very plausible that the pharmacogenetic response in AD depends upon the interaction of genes involved in drug metabolism and genes associated with AD pathogenesis. The establishment of clinical protocols for the practical application of pharmacogenetic strategies in AD will foster important advances in drug development, pharmacological optimization and cost-effectiveness of drugs, and personalized treatments in dementia.
Cacabelos
Ramón
R
EuroEspes Biomedical Research Center, Institute for CNS Disorders, 15166-Bergondo, Coruña, Spain. rcacabelos@euroespes.com
D000368:Aged; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003362:Cost-Benefit Analysis; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003704:Dementia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D003863:Depression / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D006801:Humans; D005810:Multigene Family; D010597:Pharmacogenetics / Q000191:economics / Q000193:education; D011619:Psychotropic Drugs / Q000009:adverse effects / Q000191:economics / Q000493:pharmacokinetics / Q000627:therapeutic use*
D001057:Apolipoproteins E; D002800:Cholinesterase Inhibitors; D011619:Psychotropic Drugs; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6