Researchers at Northwestern University have reported encouraging new evidence that an experimental drug may be effective as an early treatment for Alzheimer’s disease.
In their latest research, scientists uncovered a previously unrecognized and highly toxic form of amyloid beta oligomers—small clusters of peptides known to damage brain cells. This newly identified subtype appears to trigger some of the earliest pathological events in Alzheimer’s, including impaired neuronal function, inflammation, and immune cell activation.
The team found that a small-molecule compound known as NU-9 significantly reduced levels of this toxic oligomer subtype in a mouse model of Alzheimer’s disease. More importantly, NU-9 sharply limited the neurological damage associated with these early disease processes. By intervening at the very start of Alzheimer’s progression, the researchers believe NU-9 may have the potential to delay—or possibly prevent—the chain of events that eventually leads to widespread neuronal loss.
These findings suggest a promising new approach to tackling Alzheimer’s before memory loss and other severe symptoms begin.
The study is scheduled for publication on December 18 in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
“Alzheimer’s disease begins many years before clinical symptoms become visible,” explained Daniel Kranz of Northwestern University, the study’s lead author. “Long before memory problems arise, toxic amyloid beta oligomers start accumulating within neurons, and glial cells become reactive. When patients are finally diagnosed, the disease process is already well advanced. This timing may explain why so many clinical trials have been unsuccessful—they begin too late. Our work focuses on treating the disease during this early, symptom-free phase.”
Kranz recently completed his Ph.D. through Northwestern’s Interdisciplinary Biological Sciences program at the Weinberg College of Arts and Sciences, where he was mentored by William Klein, the study’s corresponding author. Klein, a professor of neurobiology at Weinberg, is also a cofounder of Acumen Pharmaceuticals, which is currently developing a monoclonal antibody aimed at the same amyloid beta oligomer subtype highlighted in the research. Another key contributor, Richard Silverman, created NU-9. Silverman is well known for inventing pregabalin (Lyrica) and serves as the Patrick G. Ryan/Aon Professor of Chemistry at Weinberg, as well as the founder of Akava Therapeutics, which is advancing NU-9—now known as AKV9—toward clinical use.
A drug with growing potential
NU-9 was first conceptualized roughly 15 years ago as part of Silverman’s long-term effort to identify small molecules capable of preventing toxic protein aggregation in neurodegenerative disorders. By 2021, the compound showed strong results in animal models of amyotrophic lateral sclerosis (ALS), where it removed harmful SOD1 and TDP-43 proteins and restored function to upper motor neurons. In 2024, NU-9 received FDA approval to enter human clinical trials for ALS.
Earlier this year, researchers including Silverman, Klein, and Kranz demonstrated that NU-9 might also be effective against Alzheimer’s disease. In that earlier study, the compound successfully cleared toxic amyloid beta oligomers in hippocampal neurons grown in the lab—cells essential for learning and memory.
“In both ALS and Alzheimer’s, toxic proteins accumulate inside cells,” said Klein. “Normally, cells have systems in place to eliminate these proteins, but those systems break down in neurodegenerative disease. NU-9 appears to restore that protective pathway.”
Targeting Alzheimer’s before symptoms begin
To explore whether NU-9 could stop damage at the earliest stages of Alzheimer’s, the researchers tested the drug in mice before symptoms developed. The animals were given NU-9 orally each day for two months. The results were dramatic.
The treatment significantly reduced early reactive astrogliosis, an inflammatory response that usually emerges long before cognitive symptoms. Researchers also observed a sharp decline in the number of toxic amyloid beta oligomers attached to astrocytes—star-shaped brain cells that help protect neurons and regulate inflammation. In addition, levels of an abnormal form of TDP-43, a protein strongly associated with neurodegeneration and cognitive decline, were greatly reduced.
“The magnitude of these effects is remarkable,” Klein said. “NU-9 had a profound impact on reactive astrogliosis, which is a central driver of early neuroinflammation in Alzheimer’s disease.”
These benefits were observed across multiple brain regions, suggesting that NU-9 exerts widespread anti-inflammatory effects.
Discovering a hidden driver of disease
While studying NU-9’s effects, the researchers uncovered an unexpected finding. Although amyloid beta oligomers have long been considered more toxic than the plaques that form later in Alzheimer’s, not all oligomers behave the same way. The team identified one particularly harmful subtype.
“We found a specific amyloid beta oligomer that appears inside neurons and on reactive astrocytes at a very early stage,” said Kranz. “This subtype may be a key trigger of early Alzheimer’s pathology.”
This subtype, known as ACU193+ because it is recognized by the ACU193 antibody, initially appears within stressed neurons. It then seems to migrate to nearby astrocytes. Once bound to these cells, the oligomers may ignite a self-propagating inflammatory response that spreads throughout the brain well before memory impairment begins.
A preventative strategy
NU-9 proved highly effective at reducing levels of this ACU193+ oligomer subtype, suggesting it could be particularly useful during the earliest phase of Alzheimer’s disease. By limiting these toxic clusters, the drug may prevent astrocytes from entering a harmful reactive state.
Although astrocytes normally act as the brain’s first line of defense, prolonged activation causes them to damage synapses, release inflammatory compounds, and accelerate neurodegeneration. Halting this process could be one of the most effective ways to slow Alzheimer’s progression.
Kranz and Silverman compared this approach to preventive strategies used in cardiovascular disease and cancer.
“People regularly monitor cholesterol to reduce future heart attack risk,” Silverman said. “High cholesterol doesn’t mean a heart attack is imminent, but it signals the need for early treatment. NU-9 could work similarly. If biomarkers indicate Alzheimer’s risk, treatment could begin before symptoms appear.”
Klein added that early diagnostic blood tests for Alzheimer’s are already under development. “The combination of improved early detection and a drug capable of stopping disease progression could be transformative.”
The research team is now evaluating NU-9 in additional Alzheimer’s models, including those that mimic late-onset disease associated with normal aging. They also plan long-term studies to determine whether treated animals remain symptom-free and to assess how early intervention influences memory and neuronal health over time.