Alzheimer’s disease: current and future therapy

This special focus issue is guest-edited by Diane Stephenson who is the Executive Director of the Coalition Against Major Diseases at the Critical Path Institute, Arizona, USA. Diane is a neuroscientist with combined experience of 30 years in academic neuroscience and drug discovery. She is passionate about translational science and has dedicated her career to the discovery of therapies to treat diseases of the nervous system. In her current role leading the Coalition Against Major Diseases, the focus is on streamlining drug development through precompetitive collaboration, data sharing and regulatory science for Alzheimer’s and Parkinson’s disease. Successes to date of Coalition Against Major Diseases serve as a prime illustration of the critical importance of collaboration.

As the population globally is aging, so does the occurrence of Alzheimer’s disease (AD) and other dementias. A devastating illness that, as yet, has no cure and is in urgent need of disease-modifying therapies.

In this special issue of Expert Review of Neurotherapeutics, we focus on AD therapy. With the recent failures in clinical trials of new therapeutics for AD, it is easy to become disheartened. There are many reasons why drug candidates do not succeed in AD. Challenges for successful approval of new therapies pose exceedingly high hurdles for drug developers. Issues such as the long duration of trials linked to the slow progression of the disease; need for safety in elderly population; lack of biomarkers that predict clinically meaningful change to enable decision making in advancing drug candidates forward; recognition that early intervention, even before onset of symptom, is required; insensitive outcome measures, patient heterogeneity and multiple confounding factors; and lack of disease-modifying therapies, all contribute to the landscape of barriers that further serve to disincentivize investments for the future. We have decided to focus on what we have learned from these trials, how we can improve our current use of therapy and what potential therapeutics look promising for the future. This issue also paves the way for groundbreaking strategies successfully employed in other complex diseases, including combination drug development.

Altaf Darvesh, Northeast Ohio Medical University, addresses the issue in his editorial on ‘Pharmacotherapy of Alzheimer’s disease: current and future trends’. Here he discusses the current limitations of AD pharmacotherapy and also discusses the investigation of the use of β-secretase inhibitors as well as immunotherapy against amyloid β protein in AD. He also delves into the recent clinical trial failures in AD and provides his insight [1].

We have a drug profile article written by George T Grossberg and colleagues of the St. Louis University School of Medicine, USA. This article looked at EVP-6124; a novel nicotinic acetylcholine receptor partial agonist, which is under investigation for the symptomatic treatment of Alzheimer’s. Looking at the data available from Phase I and II trials and looking at the ongoing Phase III clinical trial, the authors believe this to be a promising candidate for therapy in combination with cholinesterase inhibitors [2].

D Allan Butterfield from the University of Kentucky, USA, and colleagues have written a review looking at antioxidants to reduce free radical species in AD. They discuss the role of oxidative stress and other factors in the development and progression of AD and then look at the recent studies into the use of N-acetyl-l-cysteine, vitamin D, vitamin E, ferulic acid, tricyclodecan-9-yl-xanthogenate (D609), selenium and melatonin as potential therapies in AD management. The long standing role of oxidative stress is revisited with current insights [3].

Massimo Stefani and Stefania Rigacci of the University of Florence in Italy focus their review on natural phenols and highlight the importance of the search for both early diagnostic tools and preventive approaches. They discuss natural phenols found in healthy foods and their role in preventative mechanisms of action across neurodegenerative disease [4].

Atish Prakash from the ISF College of Pharmacy in Moga, India, looks at neurotransmitter abnormalities and their role in the pharmacological approach and also provides an overview of drugs currently in Phase III trials [5].

George Vradenburg, former successful business executive, influential AD patient advocate, Chairman of US Against Alzheimer’s, and founder of The Global CEO Initiative on Alzheimer’s Disease discusses the importance of global unity in fighting Alzheimer’s in his review. He discusses the national policies of France, Australia, Japan, USA and Great Britain but highlights the importance of more action to achieving the goal of prevention of AD by 2025 [6].

Harald Hampel is the AXA Chair on Alzheimer’s research at the Pierre and Marie Curie University, Paris, France, and has directed his review at targeting amyloid β and (τ). It is indicated that that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed, so he looks into what will be needed for delaying disease progression [7].

The author and colleagues contributed a review looking at the importance of combinational therapy. With the numerous failed trials in AD, there is growing recognition in the field that different groundbreaking strategies are required in order to enable success in the future. It has long been recognized that multiple pathologies beyond amyloid and tau exist in the Alzheimer’s brain early on, yet single target approaches have been the mainstay for therapeutic development. By applying examples of success from other diseases, diverse stakeholders gathered together in two seminal conferences/workshops, organized by Accelerate Cure/Treatments for. Alzheimer’s Disease, Critical Path Institute and the Alzheimer’s Association focused on combination drug development in AD. Regulatory agency leadership played a key role in supporting and outlining potential paths and the barriers are outlined candidly, with emphasis on the need for collaboration and partnerships. To conclude the issue Jesús Avila and Miguel Medina from the Center for Biomedical Research in Neurodegenerative Disease, Madrid, Spain discuss how recent advances in our understanding of tau cellular functions have unveiled novel targets for therapeutic intervention [8].

This issue represents a seminal opportunity to look across the field of AD drug development and aims to set the stage for the future.

Financial & competing interests disclosure

The author has no 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.

No writing assistance was utilized in the production of this manuscript.

Additional information

Notes on contributors

Diane Stephenson