title: Update on Alzheimer's Disease Therapy and Prevention Strategies.
abstract: Alzheimer's disease (AD) is the primary cause of age-related dementia. Effective strategies to prevent and treat AD remain elusive despite major efforts to understand its basic biology and clinical pathophysiology. Significant investments in therapeutic drug discovery programs over the past two decades have yielded some important insights but no blockbuster drugs to alter the course of disease. Because significant memory loss and cognitive decline are associated with neuron death and loss of gray matter, especially in the frontal cortex and hippocampus, some focus in drug development has shifted to early prevention of cellular pathology. Although clinical trial design is challenging, due in part to a lack of robust biomarkers with predictive value, some optimism has come from the identification and study of inherited forms of early-onset AD and genetic risk factors that provide insights about molecular pathophysiology and potential drug targets. In addition, better understanding of the Aβ amyloid pathway and the tau pathway-leading to amyloid plaques and neurofibrillary tangles, respectively, which are histopathological hallmarks of AD-continues to drive significant drug research and development programs. The main focus of this review is to summarize the most recent basic biology, biochemistry, and pharmacology that serve as a foundation for more than 50 active advanced-phase clinical trials for AD prevention and therapy.
authors.affiliation: Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY 10065; email: sakmar@rockefeller.edu.
authors.forename: W Vallen
authors.initials: WV
authors.lastname: Graham
authors.affiliation: Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY 10065; email: sakmar@rockefeller.edu.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bonito-Oliva
authors.affiliation: Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, NY 10065; email: sakmar@rockefeller.edu.|Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Sweden.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
mesh_terms: D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D008559:Memantine / Q000627:therapeutic use; D008659:Metabolic Diseases; D017628:Microglia / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism; D020078:Neurogenic Inflammation / Q000188:drug therapy; D015213:Neuroimmunomodulation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018832:Molecular Chaperones; D016875:tau Proteins; D008559:Memantine
keywords: amyloid; cognitive impairment; dementia; neurodegeneration; neurofibrillary tangle; plaque