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Alzheimer Disease Research in the 21st Century: Past and Current Failures, New Perspectives and Funding Priorities

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Alzheimer Disease Research in the 21st Century: Past and Current Failures, New Perspectives and Funding Priorities

Francesca Pistollato et al. Oncotarget.

Abstract

Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.

Keywords: Alzheimer disease; Gerotarget; animal models; computational models; human methods; induced pluripotent stem cells.

Conflict of interest statement

CONFLICTS OF INTERESTS Gillian Langley is a consultant to Humane Society International. Francesca Pistollato, Ann Lam, Neal Barnard, Mei-Chun Lai, Ryan Merkley and P. Charukeshi Chandrasekera work at the Physicians Committee for Responsible Medicine, a non-profit medical advocacy organization. Thomas J. Novak is an employee of Cellular Dynamics International (CDI) and the PI on CDI's grant with the California Institute for Regenerative Medicine (CIRM) to generate 3000 patient-derived iPSC lines, including those from patients with late-onset AD.

Figures

Figure 1
Figure 1. Bar graphs reporting the absolute numbers of AD-related projects focused on the use of animal models (black bars) vs projects accounting only for human-relevant models/methods (white bars)
A. and relative funding B., provided by the NIH from fiscal year (FY) 2007 to 2014. Analysis has been done usinghttp://projectreporter.nih.gov/reporter.cfm (as of July 6th 2015), project search was limited to ‘project terms’. List of applied keywords per category: AD & animal models: Alzheimer AND (“primate” OR “primates” OR “monkey” OR “monkeys” OR “macaca” OR “macaque” OR “marmoset” OR “vervet” OR “cercopithecus” OR “cynomolgus” OR “tamarin” OR “dog” OR “dogs” OR “canine” OR “canines” OR “canis” OR “feline” OR “felines” OR “felis” OR “guinea” OR “rabbit” OR “rabbits” OR “mouse” OR “mice” OR “porcine” OR “pig” OR “pigs” OR “ovine” OR “sheep” OR “rattus” OR “rat” OR “rats” OR “mus” OR “mice” OR “mouse” OR “mammal” OR “fish” OR “zebrafish” OR “hamster” OR “rodent” OR “animal model” OR “animals” OR “animal” OR “xenopus” OR “caenorhabditis elegans” OR “c. elegans” OR “drosophila melanogaster” OR “drosophila” OR “lamprey”). AD & human models: Alzheimer AND “human” AND (“stem cells” OR “induced pluripotent stem cells” OR “iPS” OR “imaging” OR “PET” OR “MRI” OR “computational” OR “prevention” OR “preventive strategy” OR “clinical study” OR “clinical” OR “clinical trial” OR “patient”) NOT (“primate” OR “primates” OR “monkey” OR “monkeys” OR “macaca” OR “macaque” OR “marmoset” OR “vervet” OR “cercopithecus” OR “cynomolgus” OR “tamarin” OR “dog” OR “dogs” OR “canine” OR “canines” OR “canis” OR “feline” OR “felines” OR “felis” OR “guinea” OR “rabbit” OR “rabbits” OR “mouse” OR “mice” OR “porcine” OR “pig” OR “pigs” OR “ovine” OR “sheep” OR “rattus” OR “rat” OR “rats” OR “mus” OR “mice” OR “mouse” OR “mammal” OR “fish” OR “zebrafish” OR “hamster” OR “rodent” OR “animal model” OR “animals” OR “animal” OR “xenopus” OR “caenorhabditis elegans” OR “c. elegans” OR “drosophila melanogaster” OR “drosophila” OR “lamprey”)

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