By VETTAPHARMA reporter: As Alzheimer’s disease (AD) cases surge globally—affecting more than 40 million people worldwide and projected to exceed 100 million by 2050—researchers are increasingly exploring whether existing medicines and vaccines could offer faster, safer therapeutic options.
In a 2025 Delphi consensus study published in Alzheimer’s Research & Therapy, an international expert panel evaluated drug repurposing candidates for AD, identifying three high-priority agents: the live attenuated herpes zoster vaccine (Zostavax), sildenafil, and riluzole.
Study Design
This investigation was a Delphi consensus study, representing the third iteration of an expert-driven prioritization program.
Panel Composition: 31 invited dementia experts; 23 participated.
Methodology: Anonymous nominations, systematic evidence reviews (Medline, Cochrane, PsychINFO, SCOPUS), iterative ranking rounds, and stakeholder consultation.
Initial Pool: 80 drug candidates nominated.
Shortlisted for Review: 8 candidates.
Final Priority Candidates: 3 agents met predefined mechanistic, non-clinical, clinical, and safety criteria
Patient Population Context
While this was not a clinical trial, the consensus targeted therapies suitable for:
- Individuals with established Alzheimer’s disease
- People with mild cognitive impairment (MCI) due to AD
- Older adults at risk of developing AD
The priority candidates were specifically evaluated for tolerability in older and potentially frailer populations, a key requirement for repurposed therapies in dementia
Primary Endpoints (Consensus Criteria)
Rather than traditional clinical endpoints, the study used structured consensus criteria as decision endpoints. Candidates were prioritized based on:
- Mechanistic plausibility targeting neurodegenerative pathways
- Non-clinical efficacy (animal and in vitro models)
- Human evidence, including epidemiology or early-phase clinical data
- Safety and tolerability profiles suitable for older adults
Three agents achieved consensus ranking with a median priority score of 2 (SD approximately 1.7)
Key Findings:
Herpes Zoster Vaccine (Zostavax)
Epidemiological evidence including nearly 1 million vaccinated individuals suggests a 16–20% relative reduction in incident dementia risk
A UK natural experiment involving 249,000 individuals showed a 20% relative reduction and 3.5 percentage-point reduction in new dementia diagnoses compared to unvaccinated individuals
Favorable safety profile and limited dosing requirement enhance feasibility for large-scale trials.
Sildenafil (PDE-5 inhibitor)
- Broad non-clinical evidence of cognitive benefit across multiple AD mouse models.
- Small clinical imaging studies showed improved cerebral hemodynamics and metabolic parameters, though no randomized cognitive trials have been conducted
- Epidemiological findings remain mixed.
Riluzole (Glutamate antagonist)
- Strong preclinical evidence demonstrating improved cognition in AD models.
- A 6-month Phase IIa study (n=50, probable AD, MMSE 19–27) showed protective effects on brain glucose metabolism, with numerical cognitive benefits, though underpowered for definitive conclusions
- Established safety profile in amyotrophic lateral sclerosis (ALS).
Clinical and Scientific Context
- Despite recent approvals of amyloid-targeting antibodies such as lecanemab and donanemab, therapeutic benefits remain modest and restricted to selected patient populations
Drug repurposing offers several advantages:
- Reduced development timelines
- Established safety data
- Lower trial costs
- Accessibility for academic-led investigations
The authors propose that pragmatic Phase IIb and III trials—potentially using remote or hybrid models such as the PROTECT platform—could accelerate validation of these candidates
If validated, the herpes zoster vaccine may hold potential for population-level dementia risk reduction, while sildenafil and riluzole could be explored as disease-modifying therapies in established AD
This Delphi consensus identifies three repurposed interventions with mechanistic plausibility, safety, and supportive early evidence that merit clinical testing. As traditional AD drug development remains lengthy and costly, repurposing may offer a complementary pathway toward scalable, accessible treatment strategies
Source credit:
- Corbett, A., Sultana, J., Stych, K., et. al., (2025). Drug repurposing for Alzheimer’s disease: A Delphi consensus and stakeholder consultation. Alzheimer’s Research & Therapy, 17, 237. Click here
