Translation of Pre-Clinical Studies into Successful Clinical Trials for Alzheimer’s Disease: What are the Roadblocks and How Can They Be Overcome?1

Abstract

Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

Alzheimer’s disease: experimental models and reality

“…The very poor success rate of ~99.6% with AD targeting clinical trials can in part be explained by the premature translation of successful pathology reduction in transgenic mice to humans [6, 27, 139]. Therefore, the gold standard should be to perform research using human tissue whenever possible.…”

“…Accordingly, the number of studies using AD transgenic models rapidly increased. However, questions have been increasingly raised about the validity of relying on the available transgenic models, particularly in light of the very high failure rate of clinical trials of AD therapeutics (of ~99.6%), many of which were successful in preclinical testing using these animal models [6, 27, 139]. These results highlight the often overlooked fact that these animal models do not have AD, they only recapitulate specific pathological features, most commonly in a non-physiological manner designed to allow for efficient experiments.…”

“…Importantly however, these models often lack the widespread presence of other pathological features that define AD including neuronal loss and most importantly, neurofibrillary tangle development. This lack of additional AD associated pathology could at least partly account for the lack of translation between preclinical and clinical trials [6], although there have also been a few clinical trial failures for approaches not initially tested in transgenic models[69]. As such, it is important to have a good understanding of the exact neuropathology present in each model, particularly regarding how well this correlates with human AD, so that results can be interpreted more accurately and the likelihood of translation to human studies can increase.…”

The amyloid hypothesis is too good to be true

“…I cite one more, a great paper by Banik et al [130] who "critically reviewed past literature (1990-2014)" and argued Alzheimer research and clinical trials have been "hindered by the domination of the amyloid hypothesis", and went on to write: "A greater variety of potential disease mechanisms must be entertained to enhance progress." Karran and De Strooper [21] have described some such disease mechanisms like Aβ oligomerization, neuron cell cycle re-entry, dual pathway, metabolic disorders, mitochondrial loss-offunction, and cardiovascular impairment.…”

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…In terms of target selection, we need to move from targets, such as AChE and amyloid, which have been over searched in favour of other ones with more credential for a disease-modifying effect [57]. As a recent Nature article bluntly put it, "we are over-reliant on amyloid" and "the time has come to face our fears and reject the amyloid cascade hypothesis" [58].…”