What is the gold standard model for Alzheimer’s disease drug discovery and development?

ABSTRACT

Introduction: Alzheimer’s disease models (ADMs) are currently used for drug development (DD). More than 20,000 molecules were screened for AD treatment over decades, with only one drug (Aducanumab)FDA-approved over the past 18 years. A revision of pathogenic concepts and ADMs are needed.

Areas covered: The authors discuss herein preclinical models including: (i) in vitro models (cell lines, primary neuron cell cultures, iPSC-derived brain cells), (ii) ex vivo models, and (iii) in vivo models (artificial, transgenic, non-transgenic and induced).

Expert opinion: The following types of ADMs have been reported: Mouse models (45.08%), Rat models (15.04%), Non-human Primate models (0.76%), Rabbit models (0.46%), Cat models (0.53%), Pig models (0.30%), Guinea pig models (0.15%), Octodon degu models (0.02%), Dog models (0.54%), Drosophila melanogaster models (1.79%), Zebrafish models (0.50%), Caenorhabditis elegans (1.21%), Cell culture models (3.31%), Cholinergic models (8.26%), Neurotoxic models (6.79%), Neuroinflammation models (6.92%), Neurovascular models (7.88%), and Microbiome models (0.45%).No single ADM faithfully reproduces all the pathogenic events in the human AD phenotype spectrum. ADMs should be different for (i) pathogenic studies vs basic DD, and (ii) preventive interventions vs symptomatic treatments. There cannot be an ideal ADM for DD, because AD is a spectrum of syndromes. DD can integrate pathogenic, mechanistic, metabolic, transporter and pleiotropic genes in a multisystem model.

KEYWORDS:

• Alzheimer’s disease
• animal models
• cellular models
• drug development
• genotypic models
• non-human primate models
• pharmacogenetic models
• pathogenic models
• phenotypic models
• transgenic models

Article highlights

• Over 10,000 molecules were screened for AD drug development during the past two decades with different AD animal models.

• Categories of experimental models: (i) in vitro models (cell lines, primary neuron cell cultures, iPSC-derived brain cells), (ii) ex vivo models, and (iii) in vivo models (artificial models, transgenic models, non-transgenic models and induced in vivo models).

• The most frequently used animal models for drug development: Mouse models (45.08%), Rat models (15.04%), Non-human Primate models (0.76%), Rabbit models (0.46%), Cat models (0.53%), Pig models (0.30%), Guinea pig models (0.15%), Octodon degu models (0.02%), Dog models (0.54%), Drosophila melanogaster models (1.79%), Zebrafish models (0.50%), Caenorhabditis elegans (1.21%), Cell culture models (3.31%), Cholinergic models (8.26%), Neurotoxic models (6.79%), Neuroinflammation models (6.92%), Neurovascular models (7.88%), and Microbiome models (0.45%).

• No AD model faithfully reproduces the pathogenic events present in the AD phenotype.

• Different AD models should be used for the development of new drugs focused on prevention (pre-symptomatic) versus post-symptomatic treatments.

• The ideal AD model for drug development should integrate pathogenic, mechanistic, metabolic, transporter and pleiotropic genes in a multisystem model.

Acknowledgments

The authors would like to thank their collaborators at the International Center of Neuroscience and Genomic Medicine EuroEspes, Corunna, Spain, for technical assistance.

Declaration of interest

All of the authors are employees of the EuroEspes Biomedical Research Center. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.