Discontinued disease-modifying therapies for Alzheimer’s disease: status and future perspectives

ABSTRACT

Introduction

Alzheimer’s disease (AD) is the main cause of dementia and represents a huge burden for patients, carers, and healthcare systems. Extensive efforts for over 20 years have failed to find effective disease-modifying drugs. Although amyloid-β (Aβ) accumulation in the brain predicts cognitive decline, effective reduction of plaque load by numerous drug candidates has not yielded significant clinical benefits. A similar pattern is now emerging for drugs which target hyperphosphorylated tau, and trials with anti-inflammatory drugs have been negative despite neuroinflammation appearing to have a crucial role in AD pathogenesis.

Areas covered

This article reviews key drugs that have been discontinued while in development for AD and delineates the future landscape for present and alternative approaches.

Expert opinion

Anti-Aβ drugs have failed to validate the Aβ cascade hypothesis of AD. Early findings suggest that the same is happening with therapeutics targeting tau and focussing future research solely on anti-tau drugs is inappropriate. Alternative targets should be pursued, including apolipoprotein E, immunomodulation, plasma exchange, protein autophagy and clearance, mitochondrial dysfunction, abnormal glucose metabolism, neurovascular unit support, epigenetic dysregulation, synaptic loss and dysfunction, microbiota dysbiosis, and combination therapies. Meanwhile, repurposing of drugs approved for other indications is justified where scientific rationale and robust preclinical evidence exist.

KEYWORDS:

• Alzheimer’s disease
• disease-modifying drugs
• drug repurposing
• amyloid-β
• tau protein
• neuroinflammation
• microglia
• apolipoprotein E

Article highlights

• Disease-modifying drugs for AD have been pursued for at least 20 years without any significant clinical success.

• Drugs directed against amyloid-β (Aβ), the purported initial cause of the disease, have failed both in early and advanced stages of the disease. Preventive trials with anti-Aβ drugs both in sporadic and in autosomal dominant AD forms did not produce clinically beneficial results.

• Drugs directed against tau, a major early participant the neurodegenerative process, have also failed to produce clinical benefits in initial clinical trials.

• Several traditional anti-inflammatory drugs directed against neuroinflammatory processes identified in the AD brain have also failed, both as preventive and therapeutic interventions.

• Alternative approaches to the treatment of AD have emerged in the last 5 years, some of which have already produced promising, 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.

• Drugs already approved for other clinical indications can be repurposed in the AD spectrum in the presence of an attractive scientific rationale and robust preclinical evidence.

Declaration of interest

PB Imbimbo is an employee at Chiesi Farmaceutici. He is listed among the inventors of numerous Chiesi Farmaceutici patents regarding anti-Alzheimer drugs. M Watling is a consultant at TranScrip Partners. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded