Pharmacogenomics and Epigenomics of Age-Related Neurodegenerative Disorders: Strategies for Drug Development
Age-related neurodegenerative disorders (NDDs) are polygenic/complex disorders in which genomic, epigenomic, cerebrovascular, metabolic and environmental factors converge to define a progressive neurodegenerative phenotype. Age-related pheno-genotypes in the general population are highly influenced by the individual genomic background and substantially differ from those of specific NDDs such as Alzheimer’s disease (AD) or Parkinson’s disease (PD), as prevalent prototypes of NDDs. Major determinants of therapeutic outcome in NDDs include age- and sex-related factors, pathogenic phenotype, concomitant disorders, treatment modality and polypharmacy, and pharmaco(epi)genetics. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety. Pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes represent the major genetic determinants of response to treatment in NDDs. Epigenetic changes (DNA methylation, histone modifications, miRNA dysregulation) are present in pathogenic genes associated with NDDs, and epigenetic aberrations in genes configuring the pharmacoepigenetic cascade influence the response/resistance to drugs. New pharmacological categories of anti-aging products obtained from different sources are promising candidates with potential neuroprotective effects to halt disease progression in age-related NDDs. Novel strategies in drug development, either preventive or therapeutic, for NDDs should take into consideration pharmaco(epi)genetic determinants for treatment optimization.