Pharmacogenomics and Therapeutic Strategies for Dementia

Abstract and Introduction

Abstract

Recent advances in genomic medicine have contributed to the acceleration of our understanding regarding the pathogenesis of dementia, improving diagnostic accuracy with the introduction of novel biomarkers and personalizing therapeutics with the incorporation of pharmacogenetic and pharmacogenomic procedures to drug development and clinical practice. Most neurodegenerative disorders, including Alzheimer's disease (AD), share some common features, such as a genomic background in which hundreds of genes might be involved, genome–environment interactions, complex pathogenic pathways, poor therapeutic outcomes and chronic disability. The main aim of a cost-effective treatment is to halt disease progression via modification of the functional cascade involving AD genomics, transcriptomics, proteomics and metabolomics. Unfortunately, the drugs available for the treatment of dementia are not cost effective. The pharmacological treatment of dementia accounts for 10–20% of direct costs, and fewer than 20% of the patients are moderate responders to conventional drugs, some of which may cause important adverse drug reactions. Future antidementia drugs must address the complex pathogenic niche of the disease from a multifactorial perspective. Pharmacogenetic and pharmacogenomic factors may account for 60–90% of drug variability in drug disposition and pharmacodynamics. In addition to antidementia drugs, patients with AD or with other forms of dementia need concomitant medications for the treatment of diverse disorders of the CNS associated with progressive brain dysfunction. Approximately 60–80% of drugs acting on the CNS are metabolized via enzymes of the CYP gene superfamily, and 10–20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism of many psychotropic agents. Only 26% of the patients are pure extensive metabolizers for the trigenic cluster integrated by allelic variants of the CYP2D6, CYP2C19 and CYP2C9 in combination. Although many genes have been suggested to be associated with AD, with the exception of APOE, most polymorphic variants of potential risk exhibit a very weak association with AD. APOE-4/4 carriers exhibit a dramatic biological disadvantage in comparison with other genotypes, and AD patients harboring this homozygous condition are the worst responders to conventional drugs. The incorporation of pharmacogenetic/pharmacogenomic protocols into AD research and clinical practice can foster the optimization of therapeutics by helping to develop cost-effective biopharmaceuticals and improving drug efficacy and safety.

Introduction

The lack of accurate diagnostic markers for early prediction of and effective therapy for dementia are the two most important problems to efficient diagnosis and halting of progression of the disease. Approximately 10–20% of the costs in dementia are attributed to pharmacological treatment, including antidementia drugs, psychotropics (e.g., ntidepressants, neuroleptics and anxiolytics), and other drugs currently prescribed in the elderly (e.g., antiparkinsonians, anticonvulsants, vasoactive compounds and anti-inflammatory drugs).^[1] During the past 25 years, over 300 drugs have been partially or totally developed for Alzheimer's disease (AD) with poor repercussions in public health. Despite a considerable research effort and high expenditure over more than two decades, only five drugs (tacrine, donepezil, rivastigmine, galantamine and memantine) with moderate-to-poor efficacy and questionable cost–effectiveness have been approved in developed countries, and fewer than 20% of the patients can benefit from current antidementia drugs.^[1–3]

Common features in CNS disorders include polygenic/complex disorders in which genomic and environmental factors are involved, deterioration of higher activities of the CNS, multifactorial dysfunctions in several brain circuits, and accumulation of toxic proteins in the nervous tissue in cases of neurodegeneration. For instance, the neuropathological hallmark of AD (amyloid deposition in senile plaques, neurofibrillary tangle formation and neuronal loss) is just the phenotypic expression of a pathogenic process in which different gene clusters and their products are potentially involved.^[4]

Drug metabolism, and the mechanisms underlying drug efficacy and safety, are also genetically regulated complex traits in which hundreds of genes participate cooperatively. Structural and functional genomics studies demonstrate that genomic factors, probably induced by environmental factors, cerebrovascular dysfunction and epigenetic phenomena, might be responsible for pathogenic events leading to premature neuronal dysfunction and/or death.

Pharmacogenetic and pharmacogenomic factors may account for 60–90% of drug variability in drug disposition and pharmacodynamics. Approximately 10–20% of Caucasians are carriers of defective CYP2D6 polymorphic variants that alter the metabolism of many psychotropic agents. The incorporation of pharmacogenetic/pharmacogenomic protocols into dementia research and clinical practice can foster the optimization of therapeutics by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety.^[5–11]

Expert Rev Mol Diagn. 2009;9(6):567-611. © 2009  Expert Reviews Ltd.

Cite this: Pharmacogenomics and Therapeutic Strategies for Dementia - Medscape - Sep 01, 2009.