References of experimental use of animals to model diseases, novel experimental procedures, or test novel therapeutics date all the way back to 304–258 BCE. It is undisputable that our ability to model disease in animals has provided major breakthroughs in all fields of biomedical research and has been vastly accelerated by the development of transgenic animals.

The study of neurodegenerative diseases is highly reliant on animal models due to their complexity and plurality of pathology and symptomatology. Today we have amassed a multitude of animal models, developed through genetic, chemical, and/or lesions in multiple species with the goal of faithfully mimicking these diseases and uncover the complex nature of disease-associated mechanisms. Ultimately, the goal is to test promising therapies and manage, prevent, or cure neurodegenerative disease.

The field of neurodegenerative diseases faces unique challenges in this application. First, most animal models in this area, unlike in linear diseases, do not reproduce the full phenotypical disease spectrum. Second, for a given neurodegenerative disease, the etiology and the clinical presentation differ from one patient to the next. As such, while the current models are well suited for the study of specific pathology-driven mechanisms, more notably amyloid-β, tau, or alpha-synuclein, pharmacological testing in animal models of neurodegenerative disease often translates into poorer indices of efficacy when applied to the clinical population. With these advances and challenges in mind, this handbook, written by experts in the field of neurodegeneration, provides a rich and updated overview of a wide range of animal models that are being developed and used to study complex disease dynamics, including but also beyond pathology-associated mechanisms, with the ultimate goal to discover the neuroprotective therapeutics of the future through more accurate translation of basic to clinical outputs.

The first section of this handbook presents an overview of animal models of various species, ranging from higher mammals such as primates or dogs, to knowledge gathered for more prevalent rodent genetically-based models, as well as promising models developed in the rabbit to study metabolic endpoints and therapeutic strategies for AD. Last but not least, this first section includes the review of newer invertebrate animal models, such as Drosophila to study neurodegeneration. Invertebrate models provide high-throughput potential, with highly manipulable genetics and functional output that places these models in promising standing within the field.

The second section of this handbook presents the use of animal models to pinpoint disease mechanisms. Pathology driven mechanisms are well represented but not limiting. As we are learning that “bottom-up”, overexpression based transgenic models do not provide an accurate representation of therapeutic effectiveness, we have also focused on more “top-down” models, for example those based on metabolic pathological endpoints that exclude pathology as the primary driver of neurodegenerative disease.

Lastly, this handbook concludes with a representation of various therapeutic interventions that are being used in models of neurodegenerative disease. Critical insight on effectiveness of clinically tested therapies in addition to novel, untested ones are aimed at providing both, the necessary critical due diligence when treatments fail – “where have we gone wrong” – “How can we do better” and a glimpse of hope for the future.

The Editor

The contributions in this book are based on articles previously published by IOS Press in the Journal of Alzheimer's Disease, and have in most cases been revised and updated.