Summary: Riluzole, a medication long used to slow progression in ALS, appears to slow the decline in brain metabolism and to improve cognitive measures in people with mild Alzheimer’s disease.
Source: ADDF
Riluzole, an established drug prescribed for amyotrophic lateral sclerosis (ALS) for more than two decades, showed promising results in a phase 2 pilot study in people with mild Alzheimer’s disease. Compared with placebo, riluzole-treated participants demonstrated slower decline in cerebral glucose metabolism and associated improvements in cognitive performance over a six-month treatment period.
The trial and its findings were pre-published online in the journal Brain. The Alzheimer’s Drug Discovery Foundation (ADDF) provided funding and scientific support to move this repurposing study into clinical testing.
According to study co-author Howard Fillit, M.D., ADDF’s Founding Executive Director and Chief Science Officer, “Using two types of brain scans as biomarkers allowed the team to detect improvements in brain metabolism among treated patients and to relate those imaging changes to cognitive outcomes and disease progression.”
Riluzole is thought to work by modulating glutamate, a key neurotransmitter involved in neuronal signaling. Dysregulation of glutamatergic circuits has been implicated in a toxicity cycle that contributes to Alzheimer’s disease, and targeting this pathway is an important, relatively underexplored strategy in aging and dementia research. Because riluzole is already approved for another condition, repurposing it can shorten development timelines and reduce the uncertainty around safety.
This double-blind, randomized, placebo-controlled phase 2 study enrolled 50 participants aged 50 to 95 with probable Alzheimer’s disease and Mini-Mental State Examination scores between 19 and 27. Participants were randomized to receive riluzole 50 mg twice daily (n = 26) or placebo (n = 24) for six months; 22 treated and 20 placebo participants completed the study.
The trial’s primary neuroimaging endpoint was change in cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography (FDG PET) in pre-specified regions of interest, including the posterior cingulate, precuneus, hippocampus, lateral temporal, inferior parietal and frontal cortices. The study met this primary endpoint: several regions showed significantly less decline in glucose metabolism among riluzole-treated participants than in the placebo group, with the most robust effect observed in the posterior cingulate cortex, a network hub closely associated with Alzheimer’s disease.
FDG PET changes correlated with cognitive measures; participants with better-preserved glucose metabolism tended to show smaller declines in memory, attention, language, and visuospatial abilities. Secondary outcomes also supported target engagement: magnetic resonance spectroscopy detected changes in glutamate levels in the posterior cingulate that correlated with cognitive performance, suggesting that riluzole may be modulating the glutamatergic system in vivo.
One additional primary endpoint—changes in N-acetylaspartate (NAA), a marker of neuronal viability measured with proton magnetic resonance spectroscopy—was not met in this short study. The investigators emphasize that absence of an NAA change in a six-month window does not rule out neuronal benefit over longer follow-up.
Safety outcomes showed no significant difference in adverse events between the riluzole and placebo groups. The long clinical use of riluzole for ALS provides an established safety profile that can streamline further development when repurposed for Alzheimer’s disease.
Lead investigator Dr. Ana Pereira, Assistant Professor of Neurology and Neuroscience at the Icahn School of Medicine at Mount Sinai, noted that these encouraging outcomes support advancing riluzole into a larger, longer phase 3 trial to more fully assess clinical efficacy and long-term safety.
Dr. Pereira also acknowledged the ADDF’s role in connecting the team with collaborators and novel imaging tools. In particular, ADDF facilitated a collaboration with Dawn Matthews, CEO of ADM Diagnostics, to apply advanced analytic methods to the PET data, improving the robustness of the imaging analyses.
About this Alzheimer’s disease research news
Source: ADDF
Contact: Emily Berkowitz – ADDF
Image: The image is in the public domain
Original Research: Closed access. “Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease” by Howard Fillit et al., Brain
Abstract
Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease
Dysregulation of glutamatergic neural circuits is thought to contribute to a cycle of toxicity implicated in Alzheimer’s disease. Preclinical work suggested that riluzole has potential benefits for cognition and molecular markers related to aging and Alzheimer’s disease. This pilot study evaluated riluzole’s effects in patients with mild Alzheimer’s disease using neuroimaging biomarkers.
In a six-month, double-blind, randomized, placebo-controlled phase 2 trial conducted at two sites, fifty participants meeting inclusion criteria were randomized to receive 50 mg riluzole twice daily (n = 26) or placebo (n = 24). Primary endpoints compared baseline to six-month changes in cerebral glucose metabolism (FDG PET) across predefined regions of interest and in posterior cingulate N-acetylaspartate (NAA) measured by proton magnetic resonance spectroscopy. Secondary outcomes included neuropsychological testing correlated with imaging biomarkers and in vivo measures of glutamate in the posterior cingulate as a marker of target engagement.
Riluzole-treated subjects experienced significantly less decline in cerebral glucose metabolism in multiple regions, most notably the posterior cingulate, with additional effects observed in precuneus, lateral temporal cortex, right hippocampus and frontal regions, compared with placebo. No group differences were detected for NAA levels. Changes in regional glucose metabolism correlated positively with cognitive performance, and posterior cingulate glutamate measures showed a group-by-visit interaction consistent with engagement of the glutamatergic system. These findings support further investigation of riluzole in larger and longer trials as a potential therapeutic strategy for Alzheimer’s disease.