Title:Novel Therapeutic Strategies for Dementia
Volume: 15
Issue: 2
Author(s): Ramón Cacabelos, Clara Torrellas, Iván Carrera, Pablo Cacabelos, Lola Corzo, Lucía Fernández-Novoa, Iván Tellado, Juan C. Carril and Gjumrakch Aliev
Affiliation:
Keywords:
Alzheimer disease, anti-Aβ treatments, anti-tau treatments, cholinesterase inhibitors, dementia, epigenetic drugs,
immunotherapy, natural products, pharmacogenomics, therapeutic strategies.
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.