A Delphi consensus of 23 international experts has identified three existing drugs as high-priority candidates for Alzheimer disease clinical trials, with stakeholders ranking the herpes zoster vaccine highest for acceptability and perceived benefit–risk balance.
The live attenuated herpes zoster vaccine (Zostavax), sildenafil, and riluzole emerged as co-priority candidates in the third iteration of the program, according to a review published in Alzheimer’s Research & Therapy. The agents were selected from approximately 80 nominated compounds based on mechanistic plausibility, nonclinical efficacy, and tolerability in older adults.
Methods
Anne Corbett, PhD, of the University of Exeter, and colleagues convened a panel of 23 experts from academia, clinical medicine, and the pharmaceutical industry to nominate and rank candidate drugs through an iterative Delphi process.
After removing duplicates and compounds already in phase 3 trials, shortlisted agents underwent systematic evidence review. Panelists ranked candidates anonymously using predefined consensus criteria. A parallel lay advisory group of six caregivers independently evaluated the top three candidates for acceptability, safety, and perceived benefit–risk balance.
The Three Priority Candidates
Live Attenuated Herpes Zoster Vaccine (Zostavax)
Epidemiologic evidence strongly influenced prioritization.
A systematic review of five studies including approximately 941,000 vaccinated individuals estimated a 16% relative reduction in incident dementia.
A UK natural experiment using primary care data from approximately 249,000 patients demonstrated a 20% relative reduction and a 3.5–percentage point absolute reduction in new dementia diagnoses among vaccinated individuals compared with unvaccinated controls. An Australian cohort of 101,219 patients showed a 1.8–percentage point absolute reduction using similar methods.
A separate UK cohort study of approximately 103,000 patients followed for 6 years found a 7% reduction in the composite outcome of dementia or death among recipients of the recombinant vaccine. Investigators noted that effect sizes may differ between vaccine formulations.
Proposed mechanisms include prevention of varicella-zoster virus reactivation, suppression of herpes simplex virus reactivation, immune modulation independent of pathogen effects, and enhanced antiviral cytokine responses.
Although the Delphi expert process identified all three agents as co–priority candidates, the lay advisory group ranked the live attenuated herpes zoster vaccine first, citing its established safety record and limited dosing requirements.
Sildenafil
The phosphodiesterase-5 inhibitor demonstrated broad preclinical support, with cognitive benefits reported across multiple mouse models, includingmultiple transgenic and toxin-induced mouse models of AD.
Proposed AD-relevant mechanisms include reduction of tau hyperphosphorylation, improvemed cerebral hemodynamic function, reduction of hippocampal amyloid-beta-42 levels, and modulation of nitric oxide–cyclic guanosine monophosphate signaling.
Clinical evidence remains limited. Two small imaging studies—one involving 12 patients with AD and another involving 10 patients—reported improved cerebral blood flow and attenuation of aberrant neural activity after a single dose. Neither study assessed cognitive outcomes.
Observational findings have been mixed. Two large insurance-claims analyses suggested lower AD risk among sildenafil users, whereas a Medicare-based study using multiple analytic approaches and a separate electronic medical record case-control study found no association.
No phase 3 randomized clinical trials of sildenafil have been conducted in AD.
The lay panel ranked sildenafil second, expressing moderate concern regarding the effects of long-term continuous use, given that current clinical use is typically intermittent.
Riluzole
Riluzole, a glutamate antagonist approved for amyotrophic lateral sclerosis, demonstrated cognitive rescue across several AD mouse models, including amyloid-beta–induced neuropathology, scopolamine exposure, and aged-mouse paradigms.
Mechanisms potentially relevant to AD includeModulation of glutamatergic signaling and reduction of excitotoxicity, normalization of excitatory amino acid transporter 3 expression, reduction of tau levels and amyloid-beta plaque burden, and increased brain-derived neurotrophic factor levels.
A 6-month phase 2a placebo-controlled trial in 50 patients with probable AD (Mini-Mental State Examination score 19–27) reported preservation of brain glucose metabolism compared with placebo, with the strongest signal observed in the posterior cingulate cortex. The study was not powered to detect differences in cognitive outcomes, although numerical trends favored riluzole.
Lay reviewers ranked riluzole third, citing the need for laboratory monitoring but indicating this would be acceptable if clinical benefit were demonstrated.
Compounds Not Advanced
Five additional agents — fingolimod, vortioxetine, microlithium, dasatinib, and cytisine — were not prioritized because of inconsistent preclinical evidence, safety concerns, limited central nervous system penetration, or insufficient clinical data.
Although lithium was not ranked as a priority candidate, the authors noted that subsequent research linking dementia to reduced dietary lithium intake warrants further investigation.
Proposed Trial Platform
The investigators recommend pragmatic phase 2b and phase 3 trials for all three priority candidates, including remote or hybrid designs. They identified the PROTECT platform—which coordinates cohorts totaling more than 40,000 active participants across the United Kingdom, Norway, and Canada—as a potential infrastructure for such studies.
The live attenuated herpes zoster vaccine is positioned primarily as a preventative strategy with potential population-level impact. Sildenafil and riluzole are framed as potential disease-modifying agents for patients with established clinical or preclinical AD, with sildenafil potentially relevant to individuals with concomitant cerebrovascular disease.
Limitations
The authors acknowledge that the Delphi approach favors compounds already studied and may exclude agents identifiable only through high-throughput screening. Clinical evidence for all three priority candidates remains limited to observational data or early-phase trials, and no large phase 3 randomized trials have been completed in AD for these agents.
“The combination of repurposing and efficient trial design raises the potential to fast-track multiple drug candidates through trials in an affordable way and to ensure that new treatments reach patients faster,” the investigators wrote.
Disclosures
The study authors reported disclosures as detailed in the original publication. Full disclosure information is available in the journal article.
Source: Alzheimer's Research & Therapy
