University of Exeter's Groundbreaking Study on Alzheimer's Drug Repurposing

The University of Exeter has once again positioned itself at the forefront of dementia research with a pivotal publication in Alzheimer's Research & Therapy, unveiling three promising candidates for repurposing in the fight against Alzheimer's disease (AD), the most common form of dementia. Led by Professor Anne Corbett from the College of Medicine and Health, the study employed a rigorous Delphi consensus method involving 21 international experts from academia, clinical practice, industry, and individuals affected by dementia. This collaborative effort reviewed 80 existing medications, prioritizing those with strong biological rationale, preclinical evidence, safety profiles suitable for older adults, and potential clinical benefits.

Dementia remains the United Kingdom's leading cause of death, affecting nearly one million people as of 2024, with projections estimating 1.4 million cases by 2040. Alzheimer's accounts for over half of diagnosed cases, characterized by progressive cognitive decline due to amyloid-beta plaques, tau protein tangles, neuroinflammation, and vascular changes. The urgency for new treatments is clear, as current options like amyloid-targeting antibodies offer modest benefits at high costs. Drug repurposing—adapting approved medicines for new uses—accelerates development, bypassing the 10-15 years and billions required for novel drugs.

Exeter's work highlights the university's commitment to translational research, supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre. This study builds on prior Delphi iterations, refining candidates through iterative anonymous scoring until consensus was reached, defined by median score separations exceeding 1.75 standard deviations.

Unpacking the Delphi Consensus Methodology

The Delphi method, developed in the 1960s for structured expert elicitation, ensures unbiased prioritization. Here's how it unfolded step-by-step in this study:

• Experts anonymously nominated 80 drugs from AD-related fields like immunology, vascular health, and neuroprotection.
• A triage removed duplicates, phase 3 AD trial drugs, and ineligible candidates, shortlisting seven: herpes zoster vaccine (Zostavax), sildenafil, riluzole, fingolimod, vortioxetine, micro-lithium, dasatinib, and cytisine.
• Systematic literature reviews covered biological plausibility, in vitro/animal data, early human evidence (epidemiological or pilot trials), and safety in the elderly, using databases like Medline and Scopus.
• Iterative email rounds ranked drugs on a 1-9 scale, with feedback recirculated for stability.
• A lay advisory group of six caregivers provided stakeholder input, confirming the top three via surveys and discussions.

This transparent process yielded three priority candidates: Zostavax (ranked highest by stakeholders), sildenafil (Viagra), and riluzole (motor neurone disease treatment). Professor Corbett emphasized, "Drug repurposing is vital, turning today's medicine for one condition into tomorrow's for another."

🦠 Shingles Vaccine (Zostavax): Leading Candidate for Prevention

Zostavax, a live attenuated varicella-zoster virus (VZV) vaccine approved for adults over 50 to prevent shingles (herpes zoster), emerged as the top pick. VZV, responsible for childhood chickenpox, lies dormant in sensory ganglia post-infection and reactivates as shingles in 1 in 3 people lifetime, especially over 50 due to waning immunity.

Emerging evidence links VZV reactivation to Alzheimer's pathology. Molecular studies detect VZV DNA in AD brains, correlating with amyloid formation and tau tangles. Shingles episodes increase dementia risk by 20-30% in observational data, possibly via neuroinflammation or direct neuronal damage. A meta-analysis of 941,000 individuals showed vaccination reduced dementia incidence by 16-20%.

Mechanisms include boosting VZV-specific T-cells and interferon-alpha, curbing reactivation and modulating broader immunity against amyloid-driven inflammation. Safety is exemplary—two doses suffice, with mild side effects like injection-site pain. UK rollout via NHS could enable population-level prevention. Exeter plans trials using the PROTECT platform, an online cohort of 50,000+ tracking cognition annually.

A Welsh natural experiment post-vaccination program confirmed 20% fewer new dementia diagnoses over seven years.

Sildenafil (Viagra): Boosting Brain Blood Flow and Neuroprotection

Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor marketed as Viagra for erectile dysfunction and pulmonary hypertension, ranked second. It elevates cyclic GMP (cGMP), promoting vasodilation and neuroprotection.

Preclinical models show sildenafil reduces tau hyperphosphorylation, amyloid-beta burden, and oxidative stress while enhancing synaptic plasticity and BDNF (brain-derived neurotrophic factor). Mouse studies demonstrate improved memory via GSK-3β inhibition and better cerebral oxygenation. A University of Oxford trial found single doses increased brain blood flow in vascular dementia patients, hinting at cognitive benefits.

Observational data mixed: some report 30-69% lower AD risk with chronic use, others none. Safety is favorable for intermittent dosing in elderly men and women (via pulmonary hypertension indication).Read the full study. Phase IIb/III trials are recommended.

Riluzole: Glutamate Modulation for Cognitive Preservation

Riluzole, approved for amyotrophic lateral sclerosis (ALS/motor neurone disease), inhibits glutamate release, preventing excitotoxicity—a process where excess glutamate overstimulates neurons, leading to calcium influx, tau pathology, and cell death in AD.

Animal models confirm riluzole lowers tau/Aβ, boosts BDNF, and restores memory. A phase II trial at Rockefeller University showed slower cognitive decline and preserved glucose metabolism in mild AD after six months. Proven safe in neurodegeneration, it warrants larger trials.

Exeter's PROTECT Platform: Paving Way for Future Trials

The University of Exeter co-leads PROTECT (Platform for Research in Online To Investigate Genetics and Cognition in Ageing), a NIHR-funded longitudinal study with King's College London. Enrolling over 50,000 UK adults 40+, it collects annual cognitive, genetic, and lifestyle data online, ideal for pragmatic trials of repurposed drugs like Zostavax.

This infrastructure exemplifies UK higher education's role in scalable, cost-effective research. Funded by £15M+ NIHR grants, Exeter's Biomedical Research Centre drives brain health innovations. For researchers eyeing dementia studies, opportunities abound in higher ed research jobs.

Stakeholder Views and Challenges in Repurposing

Alzheimer's Society, funders, hailed it as mirroring aspirin's heart disease success. Prof. Fiona Carragher noted, "Drug repurposing is one of the most exciting frontiers." Challenges include limited phase II/III data, nomination bias, and funding for trials. Benefits outweigh: low risk, rapid deployment.

• Risks: Mild for all (e.g., Zostavax contraindicated in immunocompromised).
• Comparisons: Vs. novel monoclonals—faster, cheaper, broader access.

Stakeholders prioritize prevention, aligning with UK's midlife risk-reduction strategies.Exeter press release.

Implications for Higher Education and Research Careers

This publication underscores UK universities' global impact in neurodegeneration. Exeter's interdisciplinary teams—spanning life sciences, data science, and clinical partnerships—exemplify collaborative higher ed. Aspiring researchers can pursue PhDs or postdocs in dementia via postdoc positions or academic CV tips.

Opportunities in NIHR-funded centres abound, fostering careers in drug discovery and trials. Explore research assistant jobs to contribute.

Photo by Adam Lemieux on Unsplash

Future Outlook: Towards Clinical Validation

Exeter eyes PROTECT-based trials for Zostavax prevention, sildenafil/riluzole modification. Success could slash UK's £42B dementia costs by 2024 projections. Balanced views: Observational data promising but causal proof needs RCTs. Multi-perspective integration ensures robust science.

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