Summary
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, meman tine), 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 vari ations 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 respond ers 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 pharma-codynamics. 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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Acknowledgments
I am thankful to all my collaborators at EuroEspes Biomedical Research Center, Institute of CNS Disorders, especially Dr. Victor Pichel, Gladys Bahamonde, Ivan Tellado, Carmen Fraile, Lola Corzo, Verónica Couceiro, Margarita Alcaraz, Laura Nebril, Cristina Muiño, and Angela Casas, as well as Dr. Lucía Fernández-Novoa, Ruth Llovo, Francisco Rocha, Ramón Alejo, Juan Carlos Carril, and Dr. Valter Lombardi at Ebiotec, Coruña, Spain, for their technical assistance. The Ebiotec Foundation provided finantial support for studies of pharmacogenomics in Alzheimer's disease.
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Cacabelos, R. (2008). Pharmacogenomics in Alzheimer's Disease. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology™, vol 448. Humana Press. https://doi.org/10.1007/978-1-59745-205-2_10
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