Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities

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.

Brain-Gut-Microbiota Axis in Alzheimer’s Disease

“…48 Recently, in light of the multi-dimensional nature of AD pathology, a potential reevaluation of the current definition of aging, cognition and their relationship to a variety of biological, social and environmental factors including the gut microbiota has been suggested. 118 An interdisciplinary approach to that complex field of host-microbiota interactions should eventually result in a strategic breakthrough in the treatment and, more importantly, in the prevention of AD.…”

Menagerie: A text-mining tool to support animal-human translation in neurodegeneration research

“…Novel discoveries, models and methods using animals constitute a significant portion of federally funded research [16] and are viewed as a means to improve drug discovery rates in the pharmaceutical industry [84]. The Investigative New Drug application (IND) represents a bridge between preclinical and clinical stages, however data in support of an IND focuses primarily on pharmacokinetic/pharmacodynamic data and toxicology, rather than efficacy [85].…”

“…In contrast to this reality, discovery literature is heavily weighted toward publication of promising studies in animals [10][11][12][13]. In the area of neurodegeneration, this translational gap has fueled skepticism regarding the validity [3,14,15] and cost [16] of preclinical animal studies.…”

Refinement on the Way Towards Replacement: Are We Doing What We Can?

“…Several unsuccessful animal models have been discussed, such as for Alzheimer disease (Cavanaugh, Pippin and Barnard, 2014;Pippin, Cavanaugh and Pistollato, 2019, Chapter 20 in this Volume;Pistollato et al, 2016), for stroke (Shuaib et al, 2007;van der Worp et al, 2010), for tuberculosis (Fonseca et al, 2017); for asthma (Mullane and Williams, 2014), for hiv/aids, for neurological, menopausal human therapy, and for cancer research as well as drug development (Pippin, 2012). Since only disease models with high predictive validity are likely to yield positive results and treatments for humans, it is critical to assess the reliability, reproducibility, and validity of the animal model first.…”