A new experimental drug from Northwestern University is showing added potential as an early treatment approach for Alzheimer’s disease.
In a new study, researchers at Northwestern reported finding a previously unrecognized, highly toxic sub-species of amyloid beta oligomers, which are toxic clusters of peptides. The team says this subtype appears to help set off some of the brain’s first Alzheimer ’s-related problems, including disrupted neuron function, inflammation, and activation of immune cells.
The drug, a small-molecule compound called NU-9, lowered levels of this toxic amyloid beta oligomer subtype and sharply reduced the harm it causes in a mouse model of Alzheimer’s disease. By targeting these early changes right as the disease begins, the researchers believe NU-9 could potentially prevent, or significantly slow, the chain of damaging events that eventually kill neurons.
Overall, the results suggest a possible new way to attack Alzheimer’s at its earliest stage, before cognitive decline and other disabling symptoms take hold.
The study will be published today (December 18) in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
“Alzheimer’s disease begins decades before its symptoms appear, with early events like toxic amyloid beta oligomers accumulating inside neurons and glial cells becoming reactive long before memory loss is apparent,” said Northwestern’s Daniel Kranz, the study’s first author. “By the time symptoms emerge, the underlying pathology is already advanced. This is likely a major reason many clinical trials have failed. They start far too late. In our study, we administered NU-9 before symptom onset, modeling this early, pre-symptomatic window.”
Who led the work and where the drug came from
Kranz recently earned his Ph.D. through the Interdisciplinary Biological Sciences (IBiS) program at Northwestern’s Weinberg College of Arts and Sciences, where he is advised by corresponding author William Klein. Klein, an Alzheimer’s researcher and professor of neurobiology at Weinberg, is also a cofounder of Acumen Pharmaceuticals.
The company has developed a therapeutic monoclonal antibody currently in clinical trials that targets the amyloid beta oligomer subtype identified in the study. Key co-author Richard Silverman invented NU-9. Silverman previously invented pregabalin (Lyrica) to treat fibromyalgia, nerve pain, and epilepsy, and he is the Patrick G. Ryan/Aon Professor in Weinberg’s Department of Chemistry. He is also founder of Akava Therapeutics, a startup company commercializing NU-9 (now called AKV9).
The promise of NU-9
First envisioned about 15 years ago, NU-9 grew out of Silverman’s long-running effort to develop a small molecule compound that could stop toxic protein aggregate buildup in neurodegenerative diseases. By 2021, NU-9 showed benefits in animal models of amyotrophic lateral sclerosis (ALS) by clearing toxic SOD1 and TDP-43 proteins and restoring health to upper motor neurons. In 2024, the U.S. Food and Drug Administration cleared the drug to begin human clinical trials for ALS.
Earlier this year, Silverman, Klein, and Kranz reported that NU-9 also might effectively treat Alzheimer’s disease. In that earlier work, NU-9 was shown to clear toxic amyloid beta oligomers in lab-grown brain cells from the hippocampus, a region essential for learning and memory.
“In both ALS and Alzheimer’s disease, cells suffer from toxic protein buildup,” Klein said. “Cells have a mechanism to get rid of these proteins, but it gets damaged in degenerative diseases like ALS and Alzheimer’s. NU-9 is rescuing the pathway that saves the cell.”
Early intervention in a pre-symptomatic Alzheimer’s mouse model
To test whether the drug could stop damage at the very start of Alzheimer’s disease, the team focused on the earliest stage. In the new study, researchers gave NU-9 to a pre-symptomatic mouse model of Alzheimer’s disease. The mice received a daily oral dose for 60 days.
The results stood out. NU-9 markedly reduced early reactive astrogliosis, an inflammatory response that usually begins well before symptoms appear. The number of toxic amyloid beta oligomers attached to astrocytes (star-shaped brain cells that protect neurons and help regulate inflammation) dropped sharply. The researchers also saw a major decrease in an abnormal form of the protein TDP-43, a hallmark of neurodegenerative diseases that has been linked to cognitive impairments.
“These results are stunning,” Klein said. “NU-9 had an outstanding effect on reactive astrogliosis, which is the essence of neuroinflammation and linked to the early stage of the disease.”
These improvements were seen across multiple brain regions, which the team says points to a brain-wide anti-inflammatory effect from NU-9.
A hidden culprit called ACU193+
As the researchers examined how NU-9 worked in the pre-symptomatic mice, they uncovered what they describe as an unexpected culprit. Scientists have long viewed amyloid beta oligomers as more harmful than the larger amyloid beta fibrils that eventually form plaques later in Alzheimer’s disease. However, the study emphasizes that amyloid beta oligomers are not all equally dangerous, and the Northwestern team identified one subtype that appears especially problematic.
“We identified a distinct amyloid beta oligomer subtype that appears inside neurons and on nearby reactive astrocytes very early in the disease,” Kranz said. “It potentially acts as an instigator of early Alzheimer’s pathology.”
The subtype is called ACU193+ because it is detected by the antibody ACU193. The researchers found that it appears early inside stressed neurons, and then these oligomers seem to move to the surfaces of nearby astrocytes. When ACU193+ oligomers attach to astrocytes, the team suggests they may help trigger an inflammatory chain reaction that spreads through the brain long before memory loss begins.
A potential prophylaxis and the cholesterol comparison
NU-9 targeted and strongly reduced this ACU193+ subtype, which the researchers say may make the drug particularly useful in the earliest stages of Alzheimer’s disease, when intervention is most effective. By lowering this subtype, NU-9 potentially could help stop astrocytes from becoming activated.
Astrocytes act as frontline responders in the brain, but when they shift into a reactive state they can become harmful. In that destructive mode, they can damage synapses, release inflammatory molecules, and speed up neurodegeneration. Preventing this shift could be one of the most powerful ways to slow Alzheimer’s progression.
Kranz and Silverman compared the strategy to early intervention used to prevent cancer and heart disease.
“Most people are used to monitoring their cholesterol levels,” Silverman said. “If you have high cholesterol, it doesn’t mean that you will have a heart attack soon. But it’s time to take drugs to lower your cholesterol levels to prevent that heart attack from happening down the road. NU-9 could play a similar role. If someone has a biomarker signaling Alzheimer’s disease, then they could start taking NU-9 before symptoms appear.”
“There are a couple early diagnostic blood tests for Alzheimer’s disease in development,” Klein added. “The promise of better early diagnostics — combined with a drug that could stop the disease in its tracks — is the goal.”
Now, the team is testing NU-9 in additional models of Alzheimer’s disease, including an animal model of late-onset disease designed to better match typical human aging. They also plan to track animals for a longer time to see whether symptoms appear in treated animals and to study how early NU-9 treatment affects memory and neuron health over time.
Reference: “Identification of a glia-associated amyloid beta oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU-9” 18 December 2025, Alzheimer’s & Dementia.
The study was supported by the National Institute of Health (grant AG061708).
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