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.
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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.Journal of Alzheimer's disease: JAD 03/2012; 30(4):745-9. DOI:10.3233/JAD-2012-112123 · 3.61 Impact Factor
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ABSTRACT: Preclinical ResearchCentral nervous system (CNS) disorders represent a major problem of health in developed countries, with important consequences in disability and health economics. Recent findings in CNS genomics and pharmacogenomics suggest that the introduction of pharmacogenomic procedures in clinical practice may help to optimize therapeutics (efficacy and safety issues). The genes involved in the pharmacogenomics of CNS drugs fall into five categories: (i) genes associated with CNS pathogenesis; (ii) genes associated with the mechanism of action of drugs; (iii) genes associated with drug metabolism; (iv) genes associated with drug transporters; and (v) pleiotropic genes involved in multifaceted cascades and metabolic reactions. Pharmacogenomics accounts for 30–90% variability in pharmacokinetics and pharmacodynamics. Only 20–30% of the Caucasian population processes normally approximately 60% of the current drugs that are metabolized via CYP2D6, CYP2C9, and CYP2C19. Clinical pharmacogenomics may contribute to personalizing pharmacological treatment, predicting patient/drug‐dose selection, minimizing drug interactions, increasing drug efficacy, and reducing unnecessary costs.Drug Development Research 12/2012; 73(8). DOI:10.1002/ddr.21039 · 0.73 Impact Factor
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ABSTRACT: Immunization against amyloid-beta-peptide (Aβ) has been widely investigated as a potential immunotherapeutic approach for Alzheimer’s disease (AD). With the aim of developing an active immunogenic vaccine without need of coadjuvant modification for human trials and therefore avoiding such side effects, we designed the Aβ1–42 vaccine (EB101), delivered in a liposomal matrix, that based on our previous studies significantly prevents and reverses the AD neuropathology, clearing Aβ plaques while markedly reducing neuronal degeneration, behavioral deficits, and minimizing neuroinflammation in APP/PS1 transgenic mice. Here, the efficacy of our immunogenic vaccine EB101 was compared with the original immunization vaccine cocktail Aβ42 + CFA/IFA (Freund’s adjuvant), in order to characterize the effect of sphingosine-1-phosphate (S1P) in the immunotherapeutic response. Quantitative analysis of amyloid burden showed a notable decrease in the neuroinflammation reaction against Aβ plaques when S1P was compared with other treatments, suggesting that S1P plays a key role as a neuroprotective agent. Moreover, EB101 immunized mice presented a protective immunogenic reaction resulting in the increase of Aβ-specific antibody response and decrease of reactive glia in the affected brain areas, leading to a Th2 immunological reaction.BioMed Research International 09/2014; 2015. DOI:10.1155/2015/807146 · 2.71 Impact Factor