Pharmacogenomics in Alzheimer's disease. Mini-Rev Med Chem 2(1):59-84

EuroEspes Biomedical Research Center, Institute for CNS Disorders, Bergondo, Coruña, Spain.
Methods in Molecular Biology (Impact Factor: 1.29). 02/2008; 448:213-357. DOI: 10.1007/978-1-59745-205-2_10
Source: PubMed


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.

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    • "The individual response to AChEI therapy is not always the same and is probably influenced by patients' genetic background as well as several other confounding factors, such as incorrect diagnosis. It is estimated that genetics accounts for 20 to 95% of variability in drug disposition and pharmacodynamics [5] [6] [7]. Donepezil is metabolized by the cytochrome P-450 (CYP) enzyme family, and the usually prescribed dosage of 10 mg/daily is generally well tolerated, giving mild and transient adverse drug reactions associated with the nervous and digestive systems [8] [9] [10]. "
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    ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder often treated with donepezil, an acetylcholinesterase inhibitor. Response to donepezil is variable, probably based on patients' genetic background in donepezil metabolizing enzymes, including cytochrome 2D6 (CYP2D6). We evaluated the association between clinical response to donepezil and a common variant (rs1080985) of CYP2D6, previously reported to be associated with poor response to the drug. In a sample of 415 AD cases, we found evidence of association between rs1080985 and response to donepezil after 6 months of therapy (OR [95% CI]: 1.74 [1.01-3.00], p = 0.04). Rs1080985 might be useful as predictor of poor response to short-term donepezil treatment.
    Full-text · Article · Mar 2012 · Journal of Alzheimer's disease: JAD
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    • "Furthermore, our method is positioned to guide future studies identifying novel drug targets and drug repositioning methods in translating genetic findings into actionable targets of drug discovery, including protein domain networks confined within biological processes that extend known canonical pathways of AD. It is established that AD therapeutics will eventually require drugs targeted to the genomic aberrations underlying the disease.53 It has been shown that drug targets and disease genes coincide within PINs,54 and further methodology has been developed and independently validated to reposition drugs in this context, in addition to similarity measures of chemical components of drugs and molecular mechanisms.55–58 "
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    ABSTRACT: Although trait-associated genes identified as complex versus single-gene inheritance differ substantially in odds ratio, the authors nonetheless posit that their mechanistic concordance can reveal fundamental properties of the genetic architecture, allowing the automated interpretation of unique polymorphisms within a personal genome. An analytical method, SPADE-gen, spanning three biological scales was developed to demonstrate the mechanistic concordance between Mendelian and complex inheritance of Alzheimer's disease (AD) genes: biological functions (BP), protein interaction modeling, and protein domain implicated in the disease-associated polymorphism. Among Gene Ontology (GO) biological processes (BP) enriched at a false detection rate <5% in 15 AD genes of Mendelian inheritance (Online Mendelian Inheritance in Man) and independently in those of complex inheritance (25 host genes of intragenic AD single-nucleotide polymorphisms confirmed in genome-wide association studies), 16 overlapped (empirical p=0.007) and 45 were similar (empirical p<0.009; information theory). SPAN network modeling extended the canonical pathway of AD (KEGG) with 26 new protein interactions (empirical p<0.0001). The study prioritized new AD-associated biological mechanisms and focused the analysis on previously unreported interactions associated with the biological processes of polymorphisms that affect specific protein domains within characterized AD genes and their direct interactors using (1) concordant GO-BP and (2) domain interactions within STRING protein-protein interactions corresponding to the genomic location of the AD polymorphism (eg, EPHA1, APOE, and CD2AP). These results are in line with unique-event polymorphism theory, indicating how disease-associated polymorphisms of Mendelian or complex inheritance relate genetically to those observed as 'unique personal variants'. They also provide insight for identifying novel targets, for repositioning drugs, and for personal therapeutics.
    Full-text · Article · Mar 2012 · Journal of the American Medical Informatics Association
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    • "An age-specific epigenetic drift associated with unusual methylation patterns in late-onset forms of AD has been identified, supporting a potential epigenetic role in the development of AD [34]. Yet, increasing lines of evidence indicate that age and hypoxia may influence epigenetic drift in AD [35]. "
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    ABSTRACT: Amyloid β-peptide (Aβ) accumulation leads to neurodegeneration and Alzheimer's disease (AD). Aβ metabolism is a dynamic process in the Aβ production and clearance that requires neprilysin (NEP) and other enzymes to degrade Aβ. It has been reported that NEP expression is significantly decreased in the brain of AD patients. Previously we have documented hypoxia is a risk factor for Aβ generation in vivo and in vitro through increasing Aβ generation by altering β-cleavage and γ-cleavage of APP and down-regulating NEP, and causing tau hyperphosphorylation. Here, we investigated the molecular mechanisms of hypoxia-induced down-regulation of NEP. We found a significant decrease in NEP expression at the mRNA and protein levels after hypoxic treatment in mouse primary cortical and hippocampal neurons. Chromatin immunoprecipitation (ChIP) assays and relative quantitative PCR (q-PCR) revealed an increase of histone H3-lysine9 demethylation (H3K9me2) and a decrease of H3 acetylation (H3-Ace) in the NEP promoter regions following hypoxia. In addition, we found that hypoxia caused up-regulation of histone methyl transferase (HMT) G9a and histone deacetylases (HDACs) HDAC-1. Decreased expression of NEP during hypoxia can be prevented by application with the epigenetic regulators 5-Aza-2'-deoxycytidine (5-Aza), HDACs inhibitor sodium valproate (VA), and siRNA-mediated knockdown of G9a or HDAC1. DNA methylation PCR data do not support that hypoxia affects the methylation of NEP promoters. This study suggests that hypoxia may down-regulate NEP by increasing H3K9me2 and decreasing H3-Ace modulation.
    Full-text · Article · Apr 2011 · PLoS ONE
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