Experts prioritize Zostavax, sildenafil and riluzole for Alzheimer disease trials

A Delphi consensus of 23 international experts has identified three existing drugs as high-priority candidates for Alzheimer disease clinical trials. The live attenuated herpes zoster vaccine (Zostavax), sildenafil, and riluzole emerged as co-priority candidates in the third iteration of the program, with stakeholders ranking the herpes zoster vaccine highest for acceptability and perceived benefit–risk balance.

The agents were selected from approximately 80 nominated compounds based on mechanistic plausibility, nonclinical efficacy, and tolerability in older adults, according to a review published in Alzheimer’s Research & Therapy. After removing duplicates and compounds already in phase 3 trials, shortlisted agents underwent systematic evidence review, and 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.

For 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, while 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. 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.

For sildenafil, the phosphodiesterase-5 inhibitor demonstrated broad preclinical support, with cognitive benefits reported across multiple mouse models, including multiple transgenic and toxin-induced mouse models of AD. Proposed AD-relevant mechanisms include reduction of tau hyperphosphorylation, improved cerebral hemodynamic function, reduction of hippocampal amyloid-beta-42 levels, and modulation of nitric oxide–cyclic guanosine monophosphate signaling. 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, although neither study assessed cognitive outcomes. Observational findings have been mixed, and no phase 3 randomized clinical trials of sildenafil have been conducted in AD.

For riluzole, a glutamate antagonist approved for amyotrophic lateral sclerosis, cognitive rescue was demonstrated across several AD mouse models, including amyloid-beta–induced neuropathology, scopolamine exposure, and aged-mouse paradigms. Mechanisms potentially relevant to AD include modulation 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 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.

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. The lay panel ranked sildenafil second, expressing moderate concern regarding the effects of long-term continuous use, while riluzole was ranked third, citing the need for laboratory monitoring but indicating this would be acceptable if clinical benefit were demonstrated.