Pharmacogenetics of Neurodegenerative disorders

Ramon Cacabelos, Carlos carril, Pablo Cacabelos, Lucia Fernández-Novoa, Meyyazhagan Arun


Neurodegenerative disorders (NDDs)[Alzheimer’s disease (AD), Parkinson’s disease (PD)] are major problems of health in developed countries. NDDs are polygenic/complex disorders in which genomic, epigenomic, cerebrovascular, metabolic and environmental factors converge to define a progressive neurodegenerative phenotype. Current drugs for NDDs are not cost-effective in some instances and most of them are not devoid of complications after chronic treatment. Pharmacogenetics contributes to optimize therapeutics in NDDs. 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. In some pharmacogenetic studies with AD-related drugs (donepezil, rivastigmine, galantamine, memantine), APOE-4 carriers are the worst responders and APOE-3 carriers are the best responders to conventional treatments. Patients harboring the TOMM40-L/L genotype in haplotypes associated with APOE-4 are the worst responders and TOMM40-S/S carriers in haplotypes with APOE-3 are the best responders. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM) and/or ultra-rapid (UM) geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM) or intermediate (IM) metabolizers. The security and safety of anti-Parkinsonian drugs [dopamine precursors (L-DOPA), dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone)] are also highly influenced by pharmacogenetic factors. In addition, epigenetic aberrations (DNA methylation, histone modifications, miRNA dysregulation) in genes configuring the pharmacoepigenetic cascade can also modify the response/resistance to drugs. Consequently, novel strategies in drug development, either preventive or therapeutic, for NDDs should take into consideration these pharmacogenetic determinants for treatment optimization.


Alzheimer’s disease, APOE, Atremorine, Epigenetics, CYPs, Neurodegenerative disorders, Parkinson’s disease, Pharmacogetics.


medical, medicine,research,pharmacology

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