Pharmacogenomics in Alzheimer's Disease

Abstract

Pharmacological treatment in Alzheimer's disease (AD) accounts for 10-20% of direct costs, and fewer than 20% of AD patients are moderate responders to conventional drugs (donepezil, rivastigmine, galantamine, memantine), with doubtful cost-effectiveness. Both AD pathogenesis and drug metabolism are genetically regulated complex traits in which hundreds of genes cooperatively participate. Structural genomics studies demonstrated that more than 200 genes might be involved in AD pathogenesis regulating dysfunctional genetic networks leading to premature neuronal death. The AD 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. AD patients also differ in their genomic architecture from patients with other forms of dementia. Functional genomics studies in AD revealed that age of onset, brain atrophy, cerebrovascular hemodynamics, brain bioelectrical activity, cognitive decline, apoptosis, immune function, lipid metabolism dyshomeostasis, and amyloid deposition are associated with AD-related genes. Pioneering pharmacogenomics studies also demonstrated that the therapeutic response in AD is genotype-specific, with apolipoprotein E (APOE) 4/4 carriers the worst responders to conventional treatments. About 10-20% of Caucasians are carriers of defective cytochrome P450 (CYP) 2D6 polymorphic variants that alter the metabolism and effects of AD drugs and many psychotropic agents currently administered to patients with dementia. There is a moderate accumulation of AD-related genetic variants of risk in CYP2D6 poor metabolizers (PMs) and ultrarapid metabolizers (UMs), who are the worst responders to conventional drugs. The association of the APOE-4 allele with specific genetic variants of other genes (e.g., CYP2D6, angiotensin-converting enzyme [ACE]) negatively modulates the therapeutic response to multifactorial treatments affecting cognition, mood, and behavior. Pharmacogenetic and pharmacogenomic factors may account for 60-90% of drug variability in drug disposition and pharmacodynamics. The incorporation of pharmacogenetic/pharmacogenomic protocols to AD research and clinical practice can foster therapeutics optimization by helping to develop cost-effective pharmaceuticals and improving drug efficacy and safety.

GOOD or BAD Responder? Behavioural and Neuroanatomical Markers of Clinical Response to Donepezil in Dementia

“…This evidence has justified the use of ACh-neurotransmission enhancing molecules in AD [6] including acetylcholinesterase inhibitors (AChEIs) which promote cholinergic neurotransmission by increasing the synaptic availability of ACh and which modulate other neurotransmitter systems as well [7][8][9].…”

Genetic association studies in patients with traumatic brain injury

“…It is possible that this pharmacogenomics approach may have a clear impact in determining the optimal therapeutic doses, minimizing the possibility of any side effects, and improving treatment adherence and efficacy. 13 In the future, all of these approaches may offer the prospect of personalized risk assessment and novel, genomic-based, targeted therapies.…”

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

“…Multiple stud ies over the past two decades have demon strated that APOE variants may affect the therapeutic response to antidementia drugs [2,3,5,6,11,12,19,[21][22][23][24][25]. At least 20 major phenotypic features illustrate the biological disadvantage of APOE-4 homozygotes and the poten tial consequences that these patients may experience when they receive pharmacological treatment for AD and/or concomitant pathologies [1][2][3]11,18,22,26]. In over 100 clinical trials for dementia, APOE has been used as the only gene of reference for the 10 [2,20,[23][24][25]27,28]; however, controversial results are frequently found due to methodological problems, study design and patient recruitment in clinical trials.…”

“…APOE is a pleio tropic gene with multifaceted activities in physiological and pathological conditions, and the presence of the APOE4 allele is determinant in AD pathogenesis [ hyperphosphorylation of tau protein and neurofibril lary tangle formation, reducing choline acetyltransfer ase activity, increasing oxidative processes, modifying inflammationrelated neuroimmunotrophic activity and glial activation, altering lipid metabolism, lipid transport and membrane biosynthesis in sprouting and synaptic remodeling and inducing neuronal apoptosis and premature neuronal death [2,3,19,20]. Multiple stud ies over the past two decades have demon strated that APOE variants may affect the therapeutic response to antidementia drugs [2,3,5,6,11,12,19,[21][22][23][24][25]. At least 20 major phenotypic features illustrate the biological disadvantage of APOE-4 homozygotes and the poten tial consequences that these patients may experience when they receive pharmacological treatment for AD and/or concomitant pathologies [1][2][3]11,18,22,26].…”

“…Major AD related pathogenic events include genomic and epigenetic defects which may lead to the phenotypic expression of extracellular Aβ deposition in senile plaques and vessels as a result of the abnormal processing of APP by secretases, intracellular neurofibrillary tangle formation due to the hyperphosphorylation of tau protein, dendritic desarborization, synaptic loss and premature neuronal death, accompanied by gliosis, microglia activation, neuroinflammatory reactions, reactive oxy gen species (ROS) generation, neurotrophic failure and neurotransmitter dysfunction [1]. This cascade of deleterious events can be dif ferentiated into primary, secondary and ter tiary pathogenic factors which can serve as candidate targets for drug development [2,3]. The genetic and epigenetic defects identi fied in AD can be classified into several cate gories: Mendelian mutations, susceptibil ity SNPs, copy number variation (CNV), mitochondrial DNA (mtDNA) mutations and epigenetic changes (DNA methylation, chromatin/histone remodeling, miRNA dys regulation) [3,4].…”