Influence of pharmacogenetic factors on Alzheimer's disease therapeutics

Alzheimer's disease (AD) is the result of the phenotypic expression of more than 200 genes which are potentially involved in neurodegeneration. Structural and functional genomics studies demonstrate that genomic factors, probably induced by environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, might be responsible for AD pathogenesis leading to premature neuronal death. Drug metabolism, pharmacokinetics and pharmacodynamics are genetically regulated complex traits in which hundreds of genes may participate. Pharmacogenetics studies show that the therapeutic response in AD is genotype specific, with APOE-4/4 carriers as the worst responders to conventional treatments. In addition, about 10-20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. With multifactorial therapies, combining different drugs, it is possible to slow down cognitive deterioration in parallel with improvement in noncognitive symptoms; however, the association of the APOE-4 allele with specific genetic variants of other genes negatively modulates the therapeutic response to multifactorial treatments affecting cognition, mood and behavior. Pharmacogenetic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenetic protocols into AD research and clinical practice can foster therapeutics optimization by improving drug efficacy and safety. Copyright (c) 2008 S. Karger AG, Basel.