Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer’s Disease: What are the Roadblocks and How Can They Be Overcome?¹

Article type: Review Article

Authors: Banik, Avijit^{a; 2} | Brown, Richard E.^{b; 2} | Bamburg, James^c | Lahiri, Debomoy K.^d | Khurana, Dheeraj^a | Friedland, Robert P.^e | Chen, Wei^f | Ding, Ying^g | Mudher, Amritpal^h | Padjen, Ante L.ⁱ | Mukaetova-Ladinska, Elizabeta^j | Ihara, Masafumi^k | Srivastava, Sudhir^l | Padma Srivastava, M.V.^m | Masters, Colin L.ⁿ | Kalaria, Raj N.^{j; *} | Anand, Akshay^{a; *}

Affiliations: [a] Neuroscience Research Lab, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India | [b] Department of Psychology and Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada | [c] Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA | [d] Departments of Psychiatry and of Medical & Molecular Genetics, Indiana University School of Medicine, Neuroscience Research Center, Indianapolis, IN, USA | [e] Department of Neurology, University of Louisville, School of Medicine, Louisville, KY, USA | [f] 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 | [g] Department of Biostatistics, University of Pittsburgh, 318C Parran Hall, Pittsburgh, PA, USA | [h] Southampton Neurosciences Group, University of Southampton, Southampton, UK | [i] Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada | [j] Institute of Neuroscience, Newcastle University, NIHR Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne, UK | [k] Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan | [l] Division of Toxicology, Central Drug Research Institute, Lucknow, India | [m] Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, India | [n] Mental Health Research Institute, University of Melbourne, Royal Parade, The VIC, Australia

Correspondence: [*] Correspondence to: Dr. Akshay Anand, Neuroscience Research Laboratory, Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. Tel.: +91 172 2756090; Fax: +91 172 2744401; E-mail: [email protected]

Correspondence: [*] Correspondence to: Prof. Raj N. Kalaria, Institute of Neuroscience, Newcastle University, NIHR Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK. [email protected]

Note: [1] Several sections of this report were conceived and formulated at the Brain Ageing and Dementia Conference, December 2012, partly sponsored by the Alzheimer’s Association, USA and Alzheimer’s Research, UK.

Note: [2] These authors contributed equally to this work.

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.

Keywords: Alzheimer’s disease, animal model, dementia, memory disorder, pre-clinical, treatment

DOI: 10.3233/JAD-150136

Journal: Journal of Alzheimer's Disease, vol. 47, no. 4, pp. 815-843, 2015