title: Novel Therapeutic Strategies for Dementia.
abstract: Dementia represents a major problem of health and disability, with a relevant economic impact on our society. Despite important advances in pathogenesis, diagnosis and treatment, its primary causes still remain elusive, accurate biomarkers are not well characterized, and the available pharmacological treatments are not cost-effective. Alzheimer disease (AD), the most prevalent form of dementia, is a polygenic/multifactorial/complex disorder in which hundreds of defective genes distributed across the human genome may contribute to its pathogenesis. Diverse environmental factors, cerebrovascular dysfunction, and epigenetic phenomena, together with structural and functional genomic dysfunctions lead to amyloid deposition, neurofibrillary tangle formation and premature neuronal death, the major neuropathological hallmarks of AD. For the past 20 years, over 1,000 different compounds have been studied as potential candidate drugs for the treatment of AD. About 50% of these substances are novel molecules obtained from natural sources. The candidate compounds can be classified according to their pharmacological properties and/or the AD-related pathogenic cascade to which they are addressed to halt disease progression. In addition to the Food and Drug Administration (FDA)-approved drugs since 1993 (tacrine, donepezil, rivastigmine, galantamine, memantine), most candidate strategies fall into 6 major categories: (i) novel cholinesterase inhibitors and neurotransmitter regulators, (ii) anti-amyloid beta (Aβ) treatments (amyloid-β protein precursor (APP) regulators, Aβ breakers, active and passive immunotherapy with vaccines and antibodies, β - and γ - secretase inhibitors or modulators), (iii) anti-tau treatments, (iv) pleiotropic products (most of them of natural origin), (v) epigenetic intervention, and (vi) combination therapies. The implementation of pharmacogenomic strategies will contribute to optimize drug development and therapeutics in AD and related disorders.
authors.affiliation: Department of Genomic Medicine, Camilo José Cela University, Villanueva de la Cañada, 28692-Madrid, Spain. rcacabelos@ucjc.edu.
authors.forename: Ramón
authors.initials: R
authors.lastname: Cacabelos
authors.forename: Clara
authors.initials: C
authors.lastname: Torrellas
authors.forename: Iván
authors.initials: I
authors.lastname: Carrera
authors.forename: Pablo
authors.initials: P
authors.lastname: Cacabelos
authors.forename: Lola
authors.initials: L
authors.lastname: Corzo
authors.forename: Lucía
authors.initials: L
authors.lastname: Fernández-Novoa
authors.forename: Iván
authors.initials: I
authors.lastname: Tellado
authors.forename: Juan C
authors.initials: JC
authors.lastname: Carril
authors.forename: Gjumrakch
authors.initials: G
authors.lastname: Aliev
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003704:Dementia / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods / Q000639:trends*; D006801:Humans; D007167:Immunotherapy / Q000379:methods / Q000639:trends
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors