Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

Abstract

The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40‐year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease‐associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs—including their bioavailability and toxicity—the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged‐related dementias. © 2019 by John Wiley & Sons, Inc.

Calcilytic NPS 2143 Reduces Amyloid Secretion and Increases sAβPPα Release from PSEN1 Mutant iPSC-Derived Neurons

“…Such compounds were highly efficacious in lowering the production of A␤ 42 in transgenic immortalized cell lines [9], but failed to exert any positive effect in human-derived neurons [10] and in clinical trials [11]. Moreover, transgenic animal models were ineffective to fully reproduce the pathological aspects of the human disease [12]. In this context, induced pluripotent stem cell (iPSC) technology provided a novel tool to overcome the limitations of transgenic systems and to alternatively approach the study of AD.…”

A 24‐week double‐blind placebo‐controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms

“…Given its procognitive and antidepressant properties, S47445 was considered as a promising candidate for the symptomatic treatment of memory deficits in patients who have a clinical diagnosis of both depression and probable AD of mild to moderate severity, even if animal models of AD presented a very poor predictive validity for the sporadic form of the human disease [38] . The study failed to demonstrate cognitive benefit on the primary outcome, although behavior improved.…”

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

“…Introduction Despite high rates of success reported in animal studies, many promising interventions for neurodegenerative and other complex diseases do not translate to effective therapies in humans [1][2][3]. Reasons for this translational gap are complex, [4] and occur at all stages of the preclinical [5,6] and clinical [7,8] continuum.…”

“…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.…”

“…Several factors that undermine the reliability of animal studies have been identified. These include insufficient rigor in animal study design and reporting [6,17], publication bias [10,12], over-reporting of significance [18,19], over-reliance on non-clinical outcome measures [20], and entrenched use of certain model systems [3,21,22]. Together, these issues contribute to poor reproducibility of animal studies, and certainly worsen the translational gap [23].…”