Alzheimer's disease therapeutic research: the path forward

The field of Alzheimer's disease therapeutic research seems poised to bring to clinic the next generation of treatments, moving beyond symptomatic benefits to modification of the underlying neurobiology of the disease. But a series of recent trials has had disappointingly negative results that raise questions about our drug development strategies. Consideration of ongoing programs demonstrates difficult pitfalls. But a clear path forward is emerging. Successful strategies will utilize newly available tools to reconsider issues of diagnosis, assessment and analysis, facilitating the study of new treatments at early stages in the disease process at which they are most likely to yield major clinical benefits.

[1]  R. Katzman.,et al.  Editorial: The prevalence and malignancy of Alzheimer disease. A major killer. , 1976, Archives of neurology.

[2]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[3]  M Haupt,et al.  [Clinical diagnosis of Alzheimer's disease]. , 1988, Deutsche medizinische Wochenschrift.

[4]  A. Smith,et al.  Use of structural imaging to study the progression of Alzheimer's disease. , 1996, British medical bulletin.

[5]  D. Selkoe,et al.  Sequence of Deposition of Heterogeneous Amyloid β-Peptides and APO E in Down Syndrome: Implications for Initial Events in Amyloid Plaque Formation , 1996, Neurobiology of Disease.

[6]  X. Chen,et al.  RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease , 1996, Nature.

[7]  A. Schmidt,et al.  RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. , 1996, Nature.

[8]  M. Raskind,et al.  Early Amyloid Deposition in the Medial Temporal Lobe of Young Down Syndrome Patients: A Regional Quantitative Analysis , 1998, Experimental Neurology.

[9]  F. Schmitt,et al.  Alzheimer neuropathologic alterations in aged cognitively normal subjects. , 1999, Journal of neuropathology and experimental neurology.

[10]  R. Motter,et al.  Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse , 1999, Nature.

[11]  A. Schmidt,et al.  The biology of the receptor for advanced glycation end products and its ligands. , 2000, Biochimica et biophysica acta.

[12]  Rong Wang,et al.  A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity , 2001, Nature.

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

[14]  Steven G Potkin,et al.  A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease , 2005, Nature Medicine.

[15]  B. Winblad,et al.  Clinical trials in mild cognitive impairment: lessons for the future , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[16]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[17]  D. Bennett,et al.  Vitamin E and donepezil for the treatment of mild cognitive impairment. , 2005, The New England journal of medicine.

[18]  D. Westaway,et al.  Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model , 2006, Nature Medicine.

[19]  T. Golde,et al.  Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice , 2007, BMC Neuroscience.

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

[21]  Gina N. LaRossa,et al.  Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans , 2006, Annals of neurology.

[22]  Nick C Fox,et al.  Longitudinal imaging in dementia. , 2007, The British journal of radiology.

[23]  J. Ávila,et al.  GSK-3 inhibitors for Alzheimer’s disease , 2007, Expert review of neurotherapeutics.

[24]  A. Fagan,et al.  Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. , 2007, Archives of neurology.

[25]  C. Morissette,et al.  Targeting soluble Aβ peptide with Tramiprosate for the treatment of brain amyloidosis , 2007, Neurobiology of Aging.

[26]  P. Scheltens,et al.  Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria , 2007, The Lancet Neurology.

[27]  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.

[28]  Jeffrey A. James,et al.  Frequent amyloid deposition without significant cognitive impairment among the elderly. , 2008, Archives of neurology.

[29]  H. Amièva,et al.  Prodromal Alzheimer's disease: Successive emergence of the clinical symptoms , 2008, Annals of neurology.

[30]  Seth Love,et al.  Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial , 2008, The Lancet.

[31]  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.

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

[33]  Bruno Vellas,et al.  Disease modifying trials in Alzheimer's disease: perspectives for the future. , 2008, Journal of Alzheimer's disease : JAD.

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

[35]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[36]  G. Zamponi Faculty Opinions recommendation of Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. , 2009 .

[37]  John W. Gilbert,et al.  Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers , 2009, Nature.

[38]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.