Recent developments in Alzheimer's disease therapeutics

Alzheimer's disease is a devastating neurological disorder that affects more than 37 million people worldwide. The economic burden of Alzheimer's disease is massive; in the United States alone, the estimated direct and indirect annual cost of patient care is at least $100 billion. Current FDA-approved drugs for Alzheimer's disease do not prevent or reverse the disease, and provide only modest symptomatic benefits. Driven by the clear unmet medical need and a growing understanding of the molecular pathophysiology of Alzheimer's disease, the number of agents in development has increased dramatically in recent years. Truly *disease-modifying' therapies that target the underlying mechanisms of Alzheimer's disease have now reached late stages of human clinical trials. Primary targets include beta-amyloid, whose presence and accumulation in the brain is thought to contribute to the development of Alzheimer's disease, and tau protein which, when hyperphosphorylated, results in the self-assembly of tangles of paired helical filaments also believed to be involved in the pathogenesis of Alzheimer's disease. In this review, we briefly discuss the current status of Alzheimer's disease therapies under study, as well the scientific context in which they have been developed.

[1]  S. Hendrix,et al.  Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial , 2008, The Lancet Neurology.

[2]  Pritam Das,et al.  NSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo , 2003 .

[3]  A. Fleisher,et al.  Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. , 2008, Archives of neurology.

[4]  Arun K. Ghosh,et al.  β-Secretase as a therapeutic target for Alzheimer’s disease , 2008, Neurotherapeutics.

[5]  Bruce H. Morimoto,et al.  NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP). , 2006, CNS drug reviews.

[6]  M. Wolfe Inhibition and modulation of γ-secretase for Alzheimer’s disease , 2008, Neurotherapeutics.

[7]  T. Gura Hope in Alzheimer's fight emerges from unexpected places , 2008, Nature Network Boston.

[8]  Pritam Das,et al.  NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. , 2003, The Journal of clinical investigation.

[9]  P. Aisen,et al.  A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease , 2008, Journal of Pharmacology and Experimental Therapeutics.

[10]  P. Aisen,et al.  A Phase II study targeting amyloid-β with 3APS in mild-to-moderate Alzheimer disease , 2006, Neurology.

[11]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

[12]  P. Fraser,et al.  Inositol Stereoisomers Stabilize an Oligomeric Aggregate of Alzheimer Amyloid β Peptide and Inhibit Aβ-induced Toxicity* , 2000, The Journal of Biological Chemistry.

[13]  P. Fraser,et al.  Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid beta peptide and inhibit abeta -induced toxicity. , 2000, The Journal of biological chemistry.

[14]  V. D’Agati,et al.  Receptor for Advanced Glycation Endproducts (RAGE): a formidable force in the pathogenesis of the cardiovascular complications of diabetes & aging. , 2007, Current molecular medicine.

[15]  K. Blennow,et al.  Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial , 2008, The Lancet Neurology.

[16]  D. Holtzman,et al.  Brain to Plasma Amyloid-β Efflux: a Measure of Brain Amyloid Burden in a Mouse Model of Alzheimer's Disease , 2002, Science.

[17]  Nick C Fox,et al.  Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial , 2005, Neurology.

[18]  X. Chen,et al.  RAGE: a potential target for Abeta-mediated cellular perturbation in Alzheimer's disease. , 2007, Current molecular medicine.

[19]  N. Relkin Current State of Immunotherapy for Alzheimer’s Disease , 2008, CNS Spectrums.

[20]  M. Roth,et al.  Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Mary Sano,et al.  Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study , 2008, The Lancet.