Translational animal models for Alzheimer's disease: An Alzheimer's Association Business Consortium Think Tank

Abstract

Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer's disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs.The purpose of the Alzheimer's Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer's therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next-generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral-cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi-model evaluation strategy to de-risk the successful transition of pre-clinical drug assets to the clinic.

Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study

“…It is worth noting that our cognitive phenotyping was limited in scope given the recent recommendations by the NIA to prioritize more translational measures, which was the focus of our resources for this project. Given that 5XFAD mice are indeed hyperactive, we were also cognizant not to conduct cognitive assays such as water maze, novel object recognition, or fear conditioning that rely on motor activity and where hyperactivity is a major confound (Sukoff Rizzo et al, 2020;Vitek et al, 2020). Thus, we highly recommend that researchers interested in using 5XFAD mice as a model of robust plaque deposition also consider the confounds related to hyperactivity in any behavioral or cognitive assay chosen, especially for studies that will investigate the potential of novel compounds for preclinical efficacy.…”

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

“…For example, the A deposits formed in the APP mouse models and in aged primates are structurally different from that in the brain from patients with AD [237]. Thus, models that better recapitulate the human AD pathology will greatly boost the AD research, such as the recent Aβ-KI mouse model of late-onset AD [28], 3 rd generation mouse model [27]; Moreover, databases of comprehensive deep phenotyping in disease animal models such as "MODEL-AD" by the Alzheimer consortium think tank [238,239] (www.model-ad.org/) are instrumental in facilitating the translational research. Systems biology approaches including single cell sequencing, transcriptomics, biochemical characterization, and behavioural assessments along with in vivo imaging data will provide accurate interpretation of the readouts [240][241][242][243].…”

Triggering Innate Immune Receptors as New Therapies in Alzheimer’s Disease and Multiple Sclerosis

“…Indeed, rodents do not develop AD and mouse models of AD are less complex and mimic the EOAD. Moreover, genetic modifications leading to the accumulation of amyloid and behavioral deficits are in poor accordance with the real-world pathology [74,75]. It is noteworthy that a lack of efficacy of antibody therapy was also reported in dogs [76], raising questions about the adequacy of our rodent models.…”