New treatment approaches for Alzheimer’s disease: preclinical studies and clinical trials centered on antidiabetic drugs

ABSTRACT

Introduction

Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) represent two major chronic diseases that affect a large percentage of the population and share common pathogenetic mechanisms, including oxidative stress and inflammation. Considering their common mechanistic aspects, and given the current lack of effective therapies for AD, accumulating research has focused on the therapeutic potential of antidiabetic drugs in the treatment or prevention of AD.

Areas covered

This review examines the latest preclinical and clinical evidence on the potential of antidiabetic drugs as candidates for AD treatment. Numerous approved drugs for T2DM, including insulin, metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium glucose cotransporter 2 inhibitors (SGLT2i), are in the spotlight and may constitute novel approaches for AD treatment.

Expert opinion

Among other pharmacologic agents, GLP-1 RA and SGLT2i have so far exhibited promising results as novel treatment approaches for AD, while current research has centered on deciphering their action on the central nervous system (CNS). Further investigation is crucial to reveal the most effective pharmacological agents and their optimal combinations, maximize their beneficial effects on neurons, and find ways to increase their distribution to the CNS.

KEYWORDS:

• Alzheimer disease
• hippocampus
• neuroprotection
• antidiabetics
• b-amyloid
• GLP-1 receptor agonists
• SGLT2 inhibitors
• T2DM
• metformin
• insulin

Article highlights

• AD and T2DM share common pathophysiologic features including inflammation, oxidative stress, and impaired glucose and insulin metabolism.

• Studies on older classes of antidiabetic drugs, such as metformin, do not consistently confirm their protective effect against AD.

• GLP-1RA and SGLT2i demonstrate the neuroprotective effect at preclinical and clinical levels affecting b-amyloid deposition and Tau phosphorylation levels.

• GLP-1RA and SGLT2i exert anti-inflammatory and antioxidant effects at the cellular level mainly via regulation of the mTOR pathway, which could ameliorate the progression of AD.

• Future research is expected to identify the antidiabetic agents or their combination with optimal and reliable effects on neurodegenerative disorders and reveal mechanisms for increased bioavailability in the CNS.

This box summarizes key points contained in the article.

Declaration of interest

SA Paschou has received honoraria and/or participated in clinical trials sponsored by NovoNordisk, Sanofi, Bausch Health, and Abbott. S Konitsiotis has received honoraria and/or participated in clinical trials sponsored by Genesis, Novartis, Merk, Teva, Abbvie, UCB, Medronic, Sanofi, and Roche. 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 project was cofinanced by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship, and Innovation, under the call RESEARCH CREATE INNOVATE (project T2EDK-02171). APK was supported by Academy of Neurosciences with a Scholarship for his doctoral studies