Early Clinical Trial Results Show an Approved ALS Drug May Have Benefits for Alzheimer’s

What: First-of-a-kind results have emerged from a small pilot clinical trial showing that riluzole, an FDA-approved drug, modulates glutamate uptake in ways that improve glucose metabolism in key brain regions in people with Alzheimer’s disease (AD), thereby improving neural functioning and cognitive performance.

Where: Matthews DC, Mao X, Dowd K et al. Riluzole, a Glutamate Modulator, Slows Cerebral Glucose Metabolism Decline in Patients with Alzheimer’s Disease. Brain. 2021: 144 (12) 3742–3755.

BrightFocus Connection: Ana Pereira, MD, of the Icahn School of Medicine at Mount Sinai received a BrightFocus Alzheimer’s Disease Research (ADR) grant to conduct the research.

Why It Is Important: Glutamate is a neurotransmitter important in learning and memory. Neurons that use glutamate are among the earliest to be damaged and lost in Alzheimer’s. The amyloid-β plaques and neurofibrillary tau tangles that accumulate in Alzheimer’s brains can contribute to the dysfunction of these cells, causing them to release excess glutamate leading to toxicity and death of neighboring cells. Dr. Pereira and her colleagues hypothesized that drugs that stabilize glutamatergic neurons might help prevent some of the neurodegeneration seen in Alzheimer’s.

Riluzole is a drug that blocks glutamate transmission. It is approved by the FDA for the treatment of amyotrophic lateral sclerosis (ALS) and has been used that way for decades. In previous work, Dr. Pereira and colleagues demonstrated in animal studies that riluzole helps prevent declines in cognition and memory. In their latest work, they did a small pilot clinical trial with early, mild Alzheimer’s patients to assess whether riluzole could improve brain function after six months of treatment.

Twenty-two participants received riluzole and 20 got a placebo. None of them had adverse effects. The researchers used PET scans to look at glucose metabolism in specific regions of the brain, a biomarker that correlates well with both glutamatergic activity and cognitive ability. After six months they found that both cerebral glucose metabolism and neuropsychological metrics declined significantly less in the treated group than in the placebo group, confirming their hypothesis.

This is the first demonstration in humans that riluzole might have a potential therapeutic benefit for people with Alzheimer’s disease.

The trial was small, but the authors note that the study “supports further exploration of the apparent disease-modifying effect of riluzole in larger, longer, full-efficacy clinical trials, with assessments of clinical and neuroimaging changes at multiple time points to map the trajectory of therapeutic response.” Their own next steps will be to stratify the Alzheimer’s patients in their own study data to analyze whether any of riluzole’s effects correlate with different clinical manifestations of AD, rates of disease progression, or comorbidities. Given that the Alzheimer’s population is so diverse in all these ways, additional analyses could provide useful information about which patients are most likely to benefit from riluzole treatment.