title: Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer's Disease: What are the Roadblocks and How Can They Be Overcome?
abstract: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
authors.affiliation: Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Avijit
authors.initials: A
authors.lastname: Banik
authors.affiliation: Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Brown
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bamburg
authors.affiliation: Departments of Psychiatry and of Medical & Molecular Genetics, Indiana University School of Medicine, Neuroscience Research Center, Indianapolis, IN, USA.
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.affiliation: Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Khurana
authors.affiliation: Department of Neurology, University of Louisville, School of Medicine, Louisville, KY, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Friedland
authors.affiliation: Division of Pulmonary Medicine, Allergy and Immunology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, University of Pittsburgh, 318C Parran Hall, Pittsburgh, PA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Southampton Neurosciences Group, University of Southampton, Southampton, UK.
authors.forename: Amritpal
authors.initials: A
authors.lastname: Mudher
authors.affiliation: Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Ante L
authors.initials: AL
authors.lastname: Padjen
authors.affiliation: Institute of Neuroscience, Newcastle University, NIHR Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Mukaetova-Ladinska
authors.affiliation: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Division of Toxicology, Central Drug Research Institute, Lucknow, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: M V
authors.initials: MV
authors.lastname: Padma Srivastava
authors.affiliation: Mental Health Research Institute, University of Melbourne, Royal Parade, The VIC, Australia.
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.affiliation: Institute of Neuroscience, Newcastle University, NIHR Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.affiliation: Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Akshay
authors.initials: A
authors.lastname: Anand
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis* / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods*; D006801:Humans; D057170:Translational Research, Biomedical / Q000379:methods*
keywords: Alzheimer’s disease; animal model; dementia; memory disorder; pre-clinical; treatment