Pharmacogenomics in Alzheimer's disease. Mini-Rev Med Chem 2(1):59-84
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.
- SourceAvailable from: Annamaria Confaloni
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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   . 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   . "
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.Journal of Alzheimer's disease: JAD 03/2012; 30(4):745-9. DOI:10.3233/JAD-2012-112123 · 4.15 Impact Factor
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ABSTRACT: β-Amyloid precursor protein cleavage enzyme (BACE) has been shown to be an attractive therapeutic target to control Alzheimer’s disease (AD). Inhibition of β-secretase enzyme can prevent the deposition of Aβ (β-amyloid) peptides, which is thought to be the major cause of AD. The present study has been considered to explore 3D-QSAR, HQSAR, and pharmacophore mapping studies of BACE inhibitors. Contour maps of 3D-QSAR studies (CoMFA: R 2 = 0.998, se = 0.067, Q 2 = 0.765, R pred2 = 0.772, r m2 = 0.739; CoMSIA: R 2 = 0.992, se = 0.125, Q 2 = 0.730, R pred2 = 0.713, r m2 = 0.687) explain the importance of steric and electrostatic, along with hydrogen-bond (HB) acceptor and donor for binding affinity to BACE. HQSAR study (R 2 = 0.941, se = 0.326, Q 2 = 0.792, R pred2 = 0.713, r m2 = 0.709) indicates the important fragments of the molecular fingerprints that might be crucial for binding affinity. Pharmacophore space modeling (R 2 = 0.937, rmsd = 0.937, Q 2 = 0.935, R pred2 = 0.709, r m2 = 0.837) describes that HB acceptor, donor, hydrophobic, and steric are the important features for interaction with receptor cavity. Finally, the models are adjudged through the docking study elucidating the interactions between the receptor and the ligand, indicating the structural requirements of potent BACE inhibitors.Medicinal Chemistry Research 10/2013; DOI:10.1007/s00044-013-0481-z · 1.61 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is a polygenic/complex disorder in which more than 50 genetic loci are involved. Primary and secondary loci are potentially responsible for the phenotypic expression of the disease under the influence of both environmental factors and epigenetic phenomena. The construction of haplotypes as genomic clusters integrating the different genotype combinations of AD-related genes is a suitable strategy to investigate functional genomics in AD. It appears that AD patients show about 3-5 times higher genetic variation than the control population. The analysis of genotype-phenotype correlations has revealed that the presence of the APOE-4 allele in AD, in conjunction with other loci distributed across the genome, influence disease onset, brain atrophy, cerebrovascular perfusion, blood pressure, beta-amyloid deposition, ApoE secretion, lipid metabolism, brain bioelectrical activity, cognition, apoptosis and treatment outcome. Pharmacogenomics studies also indicate that the therapeutic response in AD is genotype-specific and that approximately 15% of the cases with efficacy and/or safety problems are associated with a defective CYP2D6 gene. Consequently, the understanding of functional genomics in AD will foster productive pharmacogenomic studies in the search for effective medications and preventive strategies in AD.Pharmacogenomics 10/2003; 4(5):597-621. DOI:10.1517/phgs.4.5.597.23795 · 3.43 Impact Factor