Pharmacogenomics, Nutrigenomics and Therapeutic Optimization in Alzheimer’s Disease

Abstract

The molecular neuropharmacology of Alzheimer’s disease (AD) is still at an early stage. During the past 20 years, only five drugs, four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) and one NMDA receptor partial antagonist (memantine), with poor cost-effectiveness, have been approved for the treatment of AD. Patients with dementia receive many different drugs daily to palliate cognitive and noncognitive symptoms, as well as for the treatment of concomitant disorders present in the elderly population. Polypharmacy, drug–drug interactions and adverse events may combine to deteriorate the frail condition of AD patients. In recent times, the partial elucidation of the pathogenic mechanisms underlying AD-related neurodegeneration, in which many different genes are involved, has helped to foster the development of novel drugs and pharmacogenomics studies. Functional genomics studies have revealed the association of specific mutations in primary loci (APP,PS1, PS2) and/or apolipoprotein (APO)-E-related polymorphic variants with the phenotypic expression of biological traits (e.g., age at onset, brain atrophy, cognitive decline rate, β-amyloid deposition, lipid metabolism dysfunction, immunologic dysregulation or therapeutic outcome). In most pharmacogenomics studies, patients harboring the APOE-4 allele (especially homozygotes) are the worst responders. Genetic clusters integrating 3–4 AD-related genes, representing 25–30% of the AD population, have allowed the identification of selective genotype clusters of good responders. Furthermore, approximately 15% of the European population with AD show mutant CYP2D6 alleles (poor and ultrarapid metabolizers) potentially responsible for efficacy and safety problems with cholinesterase inhibitors and psychotropic drugs. Nutritional factors may also contribute to the deterioration of cognition and brain function in dementia. Novel nutraceutical products obtained from marine sources with biotechnologic procedures have demonstrated atheroprotective properties and lipid-lowering effects and are devoid of hepatotoxic activity. Some of these nutraceuticals exhibit a genotype-dependent therapeutic effect, reflecting a nutrigenomic profile. Nutrigenetics/nutrigenomics- and pharmacogenetics/pharmacogenomics-associated factors may represent major determinants of drug efficacy and safety and therapeutics optimization in dementia and other CNS disorders.