Should drug discovery scientists still embrace the amyloid hypothesis for Alzheimer’s disease or should they be looking elsewhere?

ABSTRACT

Introduction

Alzheimer’s Disease (AD) represents a large and growing challenge to patients, carers and healthcare systems, yet extensive efforts to develop therapeutics to modify its course have been met with repeated failure in recent decades. Although the evident presence of accumulated β-amyloid (Aβ) in AD brains has singled it out as an obvious therapeutic target, the effective reduction of plaque load or soluble Aβ by numerous drug candidates has not produced commensurate clinical benefits – calling into question the Aβ cascade hypothesis of AD. A similar path is now unfolding in the pursuit of therapeutics targeting hyperphosphorylated tau-comprised neurofibrillary tangles.

Areas covered

This perspective reviews the basis of the Aβ cascade hypothesis of AD and how clinical trials of anti-Aβ drugs have failed to support it, and reflects upon the early findings suggesting that a similar path is being followed with therapeutics targeting tau. Other potential approaches to identifying therapeutics for AD are explored herein.

Expert opinion

The relevance of the Aβ cascade hypothesis to the development of therapeutics for AD appears disproven. Drugs targeting tau appear to be suffering the same fate but may yet produce better results. Alternative approaches are being pursued, some of them with initial small-scale, but promising, results.

KEYWORDS:

• Β-amyloid
• tau
• neuroinflammation
• microglia
• ApoE

Article highlights

• Alzheimer’s disease (AD) is a neurodgenerative disorder that causes around 70% of cases of demenia.

• The numerous failed clinical trials in both early and advanced stages of the Alzheimer continuum of a plethora of anti-Aβ therapeutics have questioned the validity of the Aβ cascade hypothesis of AD. Further clinical studies with monoclonal antibodies directed against oligomeric forms of Aβ are being pursued.

• Initial clinical studies with anti-tau drugs have also been negative, but research has still to determine which specific forms of tau are neurotoxic and should be targeted by selective agents.

• Numerous alternative approaches to the treatment of AD are evident, some having already produced positive, if limited, results in early therapeutic trials.

• Future research efforts must encompass such alternative approaches, in addition to the anti-tau approach, in order to maximize the chances of successful outcomes for patients with this burdensome disease.

This box summarizes key points contained in the article.

Declaration of interest

B Imbimbo is an employee of Chiesi Farmaceutici and is listed as an inventor of a number of Alzheimer’s drug patents belonging to Chiesi. M Watling is an employee of Transcrip Partners LLP. 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

One referee is affiliated with Biomarkable BV while another referee is an employee and officer of TauRx Pharmaceuticals Ltd and an inventor on patents relating to tau-aggregation inhibitors that are owned by WisTa Laboratories Ltd., an affiliate of TauRx. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors are supported by Chiesi Farmaceutici