Successful therapies for Alzheimer's disease: why so many in animal models and none in humans?

Abstract

Peering into the field of Alzheimer's disease (AD), the outsider realizes that many of the therapeutic strategies tested (in animal models) have been successful. One also may notice that there is a deficit in translational research, i.e., to take a successful drug in mice and translate it to the patient. Efforts are still focused on novel projects to expand the therapeutic arsenal to "cure mice." Scientific reasons behind so many successful strategies are not obvious. This article aims to review the current approaches to combat AD and to open a debate on common mechanisms of cognitive enhancement and neuroprotection. In short, either the rodent models are not good and should be discontinued, or we should extract the most useful information from those models. An example of a question that may be debated for the advancement in AD therapy is: In addition to reducing amyloid and tau pathologies, would it be necessary to boost synaptic strength and cognition? The debate could provide clues to turn around the current negative output in generating effective drugs for patients. Furthermore, discovery of biomarkers in human body fluids, and a clear distinction between cognitive enhancers and disease modifying strategies, should be instrumental for advancing in anti-AD drug discovery.

Keywords: adrenergic receptors; biomarkers; lost-in-translation research; resveratrol; transgenic AD models.

FIGURE 1

Cartoonial metaphor of the success in relieving the cognitive deficits of AD mouse models. A variety of different compounds are proven successful as cognitive enhancers and neuroprotetive in transgenic AD models. Copyright retained by Nuria Franco (franconuria@gmail.com).

FIGURE 2

Scheme of etiological factors and challenges in AD research. Pathogenesis: epidemiological and genetic findings uncovered several major mechanisms leading to AD pathogenesis. Main AD pathological hallmarks are deposition of Aβ and p-tau in the brain. It is unquestionable that AD starts with Aß pathogenesis in familial AD (FAD) cases. The current knowledge suggests that tau pathology is a later event in the disease.