Pharmacogenetic basis for therapeutic optimization in Alzheimer's disease.

Alzheimer's disease is a major health problem in developed countries. 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 antidementia drugs, with questionable cost effectiveness. The phenotypic expression of Alzheimer's disease is characterized by amyloid deposition in brain tissue and vessels (amyloid angiopathy), intracellular neurofibrillary tangle formation, synaptic and dendritic loss, and premature neuronal death. Primary pathogenic events underlying this neurodegenerative process include genetic factors involving more than 200 different genes distributed across the human genome, accompanied by progressive cerebrovascular dysfunction, and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PSEN1, PSEN2) are present in less than 5% of the Alzheimer's disease population; however, the presence of the epsilon4 allele of the apolipoprotein E gene (APOE) 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 and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for between 20% and 95% of the variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in Alzheimer's disease is genotype specific, depending on genes associated with Alzheimer's disease pathogenesis and/or genes responsible for drug metabolism (e.g. cytochrome P450 [CYP] genes). In monogenic studies, APOEepsilon4/epsilon4 genotype carriers are the worst responders to conventional treatments. Some cholinesterase inhibitors currently being use in the treatment of Alzheimer's disease are metabolized via CYP-related enzymes. These drugs can interact with many other drugs that are substrates, inhibitors or inducers of the CYP system, this interaction eliciting liver toxicity and other adverse drug reactions. CYP2D6 enzyme isoforms are involved in the metabolism of more than 20% of drugs used in CNS disorders. The distribution of the CYP2D6 genotypes in the European population of the Iberian peninsula differentiates four major categories of CYP2D6-related metabolizer types: (i) extensive metabolizers (EM) [51.61%]; (ii) intermediate metabolizers (IM) [32.26%]; (iii) poor metabolizers (PM) [9.03%]; and (iv) ultra-rapid metabolizers (UM) [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 pharmacologic treatments in Alzheimer's disease. At this early stage of the development of pharmacogenomic/pharmacogenetic procedures in Alzheimer's disease therapeutics, it seems very plausible that the pharmacogenetic response in Alzheimer's disease depends on the interaction of genes involved in drug metabolism and genes associated with Alzheimer's disease pathogenesis.