Pharmacogenomics and therapeutic prospects in Alzheimer’s disease

Abstract

Approximately 10 – 20% of the direct costs of Alzheimer’s disease are attributed to pharmacological treatment. Less than 20% of Alzheimer’s disease patients are moderate responders to conventional drugs (e.g., donepezil, rivastigmine, galantamine, memantine) with doubtful cost-effectiveness. In total, 15% of the Caucasian population with Alzheimer’s disease are carriers of defective CYP2D6 polymorphic variants that are potentially responsible for therapeutic failures when receiving cholinesterase inhibitors and psychotropic drugs. In addition, structural genomics studies demonstrate that > 100 genes might be involved in Alzheimer’s disease pathogenesis, regulating dysfunctional genetic networks leading to premature neuronal death. The Alzheimer’s disease population exhibits a higher genetic variation rate than the control population, with absolute and relative genetic variations of 40 – 60% and 0.85 – 1.89%, respectively. Alzheimer’s disease patients also differ from patients with other forms of dementia in their genomic architecture, possibly with different genes acting synergistically to influence the phenotypic expression of biological traits. Functional genomics studies in Alzheimer’s disease reveal that age of onset, brain atrophy, cerebrovascular haemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function and amyloid deposition are associated with Alzheimer’s disease-related genes. Pioneering pharmacogenomics studies also demonstrate that the therapeutic response in Alzheimer’s disease is genotype-specific, with APOE-4/4 carriers as the worst responders to conventional treatments. It is likely that pharmacogenetic and pharmacogenomic factors account for 60 – 90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenomic/pharmacogenetic protocols in Alzheimer’s disease may foster therapeutic optimisation by helping to develop cost-effective drugs, improving efficacy and safety, and reducing adverse events and cutting-down unnecessary cost for the industry and the community.

Keywords::

• Alzheimer’s disease
• cholinesterase inhibitors
• functional genomics
• genetics
• genomics
• genotype–phenotype correlations
• multifactorial therapy
• pharmacogenetics
• pharmacogenomics