title: Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics.
abstract: Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.
authors.affiliation: EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, EuroEspes Chair of Biotechnology and Genomics, Camilo José Cela University, 15165 Bergondo, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Cacabelos
authors.forename: Rocío
authors.initials: R
authors.lastname: Martínez
authors.forename: Lucía
authors.initials: L
authors.lastname: Fernández-Novoa
authors.forename: Juan C
authors.initials: JC
authors.lastname: Carril
authors.forename: Valter
authors.initials: V
authors.lastname: Lombardi
authors.forename: Iván
authors.initials: I
authors.lastname: Carrera
authors.forename: Lola
authors.initials: L
authors.lastname: Corzo
authors.forename: Iván
authors.initials: I
authors.lastname: Tellado
authors.forename: Jerzy
authors.initials: J
authors.lastname: Leszek
authors.forename: Adam
authors.initials: A
authors.lastname: McKay
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda